Materiały źródłowe

• #1 ALS Pathogenesis and Therapeutic Approaches: The Role of Mesenchymal Stem Cells and Extracellular Vesicles

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5359305/

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive muscle paralysis determined by the degeneration of motoneurons in the motor cortex brainstem and spinal cord. The ALS pathogenetic mechanisms are still unclear, despite the wealth of studies demonstrating the involvement of several altered signaling pathways, such as mitochondrial dysfunction, glutamate excitotoxicity, oxidative stress and neuroinflammation. […] The involvement of different mechanisms in ALS pathogenesis underlines the need for a therapeutic approach targeted to multiple aspects. […] The identification of molecular mechanisms by which motoneurons degenerate in ALS is crucial for understanding disease progression and for the development of new therapeutic approaches. Although SOD1 mutations have been linked to ALS since more than two decades, the mechanisms underlying the mode of action of mutant SOD1 and the subsequent neurodegeneration/neurotoxicity are still unclear. Several hypotheses have been proposed in this regards and it seems likely that the combination of mechanisms, rather than a single mechanism, contributes to neurodegeneration in ALS, pointing to a multifactorial pathogenesis.

• #2 Amyotrophic Lateral Sclerosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK556151/

  Amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, is the most common motor neuron disease (MND) in a group of illnesses that involve both upper and lower motor neurons. ALS is a progressive neurodegenerative disorder that causes motor neuron degeneration and death, resulting in muscle weakness and respiratory failure. […] With both sporadic and familial forms, a single and precise etiology of amyotrophic lateral sclerosis is lacking. There are multiple genetic and environmental proposed causes. ALS is incurable, and treatment focuses on symptom management and addressing family and caregiver stress. […] The etiology of ALS is unknown. Numerous possible genetic and sporadic possibilities are suggested. Amyotrophic lateral sclerosis most commonly begins with signs of LMN degeneration affecting the upper extremity but can also present as UMN or bulbar symptoms. […] A single and precise etiology governing ALS is lacking. The possible mechanisms described in the literature are genetic mutations, oxidative stress, excitotoxicity, mitochondrial and proteasomal dysfunctions, altered synaptic function, disturbed axonal transport, and neuroinflammation. […] It appears that ALS develops as a result of the interaction between both genetic and environmental factors.

• #3 Amyotrophic lateral sclerosis (ALS) – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/amyotrophic-lateral-sclerosis/symptoms-causes/syc-20354022

  ALS affects the nerve cells that control voluntary muscle movements such as walking and talking. These nerve cells are called motor neurons. There are two groups of motor neurons. The first group extends from the brain to the spinal cord to muscles throughout the body. They’re referred to as upper motor neurons. The second group extends from the spinal cord to muscles throughout the body. They’re referred to as lower motor neurons. […] ALS causes both groups of motor neurons to gradually deteriorate and then die. When motor neurons are damaged, they stop sending messages to the muscles. As a result, the muscles can’t function. […] Researchers continue to study possible causes of ALS. Most theories center on a complex interaction between genes and factors in the environment.

• #4

  https://journals.lww.com/nrronline/fulltext/2024/05000/pathological_mechanisms_of_amyotrophic_lateral.32.aspx

  Amyotrophic lateral sclerosis refers to a neurodegenerative disease involving the motor system, the cause of which remains unexplained despite several years of research. […] According to current research, amyotrophic lateral sclerosis is likely not due to a single factor but rather to a combination of mechanisms mediated by complex interactions between molecular and genetic pathways. […] The progression of the disease involves multiple cellular processes and the interaction between different complex mechanisms makes it difficult to identify the causative factors of amyotrophic lateral sclerosis. […] Here, we review the most common amyotrophic lateral sclerosis-associated pathogenic genes and the pathways involved in amyotrophic lateral sclerosis, as well as summarize currently proposed potential mechanisms responsible for amyotrophic lateral sclerosis disease and their evidence for involvement in amyotrophic lateral sclerosis.

• #5 Advances and challenges in understanding the multifaceted pathogenesis of amyotrophic lateral sclerosis

  https://smw.ch/index.php/smw/article/download/1990/2861?inline=1

  Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease, which primarily affects motor neurons leading to progressive paralysis and death within a few years from onset. The pathological hallmark of ALS is the presence of cytoplasmic ubiquitinated protein inclusions in motor neurons and glial cells primarily in the spinal cord. […] However, much more needs to be done, as the pathogenic mechanisms triggered by a genetic or sporadic event leading to cytotoxicity and neuronal cell death are still poorly understood. […] The pathologic hallmark of ALS is the presence of ubiquitinated protein inclusions in motor neurons and glial cells primarily of the spinal cord and motor cortex. The major protein component of these inclusions is different in the various types of ALS, highlighting the heterogeneity of the disease.

• #6

  https://www.omim.org/entry/105400

  A number sign (#) is used with this entry because 15 to 20% of cases of familial amyotrophic lateral sclerosis (FALS), referred to here as ALS1, are associated with mutations in the superoxide dismutase-1 gene (SOD1; 147450) on chromosome 21q22. Although most cases of SOD1-related familial ALS follow autosomal dominant inheritance, rare cases of autosomal recessive inheritance have been reported. […] Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. ALS usually begins with asymmetric involvement of the muscles in middle adult life. Approximately 10% of ALS cases are familial (Siddique and Deng, 1996). […] Ranganathan et al. (2020) provided a detailed review of the genes involved in different forms of ALS with FTD, noting that common disease pathways involve disturbances in RNA processing, autophagy, the ubiquitin proteasome system, the unfolded protein response, and intracellular trafficking. The current understanding of ALS and FTD is that some forms of these disorders represent a spectrum of disease with converging mechanisms of neurodegeneration.

• #7 Amyotrophic Lateral Sclerosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK556151/

  Over 120 genes have been implicated in ALS. A prevailing thought is that the accumulation of abnormal proteins due to aberrant RNA processing is involved in the development of ALS. […] The accumulation of TDP-43 is present in most cases of sporadic ALS, FTD, ALS-FTD, and some cases of familial ALS. […] The interplay of epigenetics (ie, a modification of gene expression rather than a modification of the genetic code itself), a trigger factor (risk variables described above), a propagating channel (oxidative stress, excitotoxicity, defective RNA processing, intraneuronal protein aggregates, mitochondrial dysfunction, neuroinflammation, or protein misfolding) and final clinical manifestations have also been advocated.

• #8

  https://omim.org/entry/105400

  A number sign (#) is used with this entry because 15 to 20% of cases of familial amyotrophic lateral sclerosis (FALS), referred to here as ALS1, are associated with mutations in the superoxide dismutase-1 gene (SOD1; 147450) on chromosome 21q22. Although most cases of SOD1-related familial ALS follow autosomal dominant inheritance, rare cases of autosomal recessive inheritance have been reported. […] Amyotrophic lateral sclerosis is a neurodegenerative disorder characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. ALS usually begins with asymmetric involvement of the muscles in middle adult life. […] Ranganathan et al. (2020) provided a detailed review of the genes involved in different forms of ALS with FTD, noting that common disease pathways involve disturbances in RNA processing, autophagy, the ubiquitin proteasome system, the unfolded protein response, and intracellular trafficking. The current understanding of ALS and FTD is that some forms of these disorders represent a spectrum of disease with converging mechanisms of neurodegeneration.

• #9 Pathophysiology of Amyotrophic Lateral Sclerosis | IntechOpen

  https://www.intechopen.com/chapters/45326

  Despite of all these discoveries the etiology of ALS remains elusive. A number of potential pathogenic mechanisms have been associated with ALS including excitotoxicity, mitochondrial dysfunction, apoptosis, glial activation, RNA-processing, growth factor abnormalities, etc. These potential pathogenic processes are reviewed in this chapter. […] The hallmark finding of lower motor neuron (LMN) pathology in ALS is the presence of intracellular inclusion bodies in neuronal soma and proximal dendrites as well as glia (Barbeito et al., 2004). […] Mutations in the gene of copper/zinc superoxide dismutase type 1 (SOD1) are the most common cause of fALS (Rothstein, 2009; Boillee and Cleveland, 2008; Robberecht and Phillips, 2013). […] Recent reports indicate that SOD1 mutations may also be the cause of between 0.7 – 4% cases of sporadic ALS (sALS) (Robberecht and Phillips, 2013).

• #10

  https://journals.lww.com/annalsofian/fulltext/2011/14040/altered_rna_metabolism_and_amyotrophic_lateral.3.aspx

  Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults. […] The biologic basis of the disease is unknown. However, ALS research has taken a dramatic turn over the last 3 years. Landmark discoveries of mutations in the transactive response DNA-binding protein (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS) as causative of ALS and demonstration that abnormal aggregation of these proteins is the proximate cause of motor neuron loss in familial and sporadic ALS have initiated a paradigm shift in understanding the pathogenic mechanism of this disease. […] A major shift in our understanding of ALS pathogenesis occurred in 2006, with the identification of a 43-kDa transactive response (TAR) DNA-binding protein (TDP-43) as a key pathological substrate of cytosolic inclusions in sALS and frontotemporal lobe degeneration with ubiquitin inclusions (FTLD-U).

• #11

  https://journals.lww.com/annalsofian/fulltext/2011/14040/altered_rna_metabolism_and_amyotrophic_lateral.3.aspx

  The identification of TDP-43 mutations was in tandem followed by the discovery of mutations in another RNA/DNA-binding protein FUS/TLS (fused in sarcoma and translocated in liposarcoma) in 2009, as a primary cause of fALS. […] Taken together, the emerging concept that ALS is a RNA-processing disorder is taking a tangible shape. […] This review summarizes the literature pertaining to recently identified TDP-43 and FUS/TLS mutations as RNA-processing errors in ALS and its implication in understanding the pathogenic mechanism of the disease and possible future therapies. […] The mounting evidence over the last 3 years strongly implicates TDP-43 and FUS/TLS in motor neuron degeneration in ALS through errors in multiple steps of RNA processing. […] The major question underlying ALS pathogenesis that needs resolution: Is ALS from TDP-43 or FUS/TLS mutation caused by the loss of normal function or gain of one or more toxic properties, or both?

• #12 Pathophysiology of Amyotrophic Lateral Sclerosis | IntechOpen

  https://www.intechopen.com/chapters/45326

  Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by death of pyramidal neurons in the motor cortex (upper motor neurons) and motor neurons in the brain stem and central spinal cord (lower motor neurons). This results in muscle weakness, progressive motor disability, and finally death by respiratory failure or an associated infection (Shook and Pioro, 2009). […] In the last few years, there had been an explosion of genetic studies associating ALS with several genetic mutations in genes codifying for different proteins: Cu/Zn superoxide dismutase, (SOD1), transactive response binding protein 43 (TARDBP), fused in sarcoma (FUS), and valosin containing protein (VCP). Most recently, a genetic defect was identified with an expansion of the noncoding GGGGCC hexanucleotide repeat in the chromosome 9, open reading frame 72 (C9ORF72), associated with ALS with and without frontotemporal dementia (Boeve et al., 2012).

• #13 The pathophysiology of amyotrophic lateral sclerosis (ALS) and the role of C9orf72

  https://www.linkedin.com/pulse/pathophysiology-amyotrophic-lateral-sclerosis-als-role-hoffman

  Amyotrophic lateral sclerosis (ALS) is a disastrous neurodegenerative disorder, where people die within 3-5 years after they were diagnosed, mostly due to respiratory failure. In ALS, motor neurons in the spinal cord, brainstem and motor cortex degrade (motor neuron dysfunction). […] ALS is considered to be a complex genetic disorder: there is a combination of multiple genes and environmental exposure needed for the person to be susceptible. […] With the gene C9orf72, patients carry hexanucleotide (GGGGCC) repeat expansions (HRE) in the first intronic region (of chromosome 9 open reading frame 72 gene) (C9orf72). […] Even though there are these new insights, the exact pathophysiological mechanism in ALS is unknown. […] In this section, I describe the pathophysiology of growth factors, neurotrophic factors, mitochondrium, axonal transport, oxidative stress, excitotoxicity, inflammation, apoptosis and what it has to do with ALS.

• #14 Why do motor neurons degenerate? Actualisation in the pathogenesis of amyotrophic lateral sclerosis | Neurología (English Edition)

  https://www.elsevier.es/en-revista-neurologia-english-edition-495-articulo-why-do-motor-neurons-degenerate-S2173580817301633

  Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons. Although a small proportion of ALS cases are familial in origin and linked to mutations in specific genes, most cases are sporadic and have a multifactorial aetiology. Some recent studies have increased our knowledge of ALS pathogenesis and raised the question of whether this disorder is a proteinopathy, a ribonucleopathy, an axonopathy, or a disease related to the neuronal microenvironment. […] ALS pathogenesis has not been fully elucidated. Recent studies suggest that although initial triggers may differ among patients, the final motor neurons degeneration mechanisms are similar in most patients once the disease is fully established. […] ALS specifically affects cells, leading to tissue alterations; the most frequently affected cells are motor neurons. Although the precise factors determining preferential involvement of motor neurons are yet to be fully understood, certain factors have been associated with the particular vulnerability of these cells: (1) the large size of the cells and their robust cytoskeleton, which has high metabolic demands to maintain cell functions; (2) high reliance on optimal mitochondrial function; (3) high vulnerability to excitotoxicity and dysregulation of intracellular calcium homeostasis; and (4) reduced capacity for heat shock response and chaperone activity, and possibly reduced function of the ubiquitin proteasome system.

• #15 Pathophysiology of Amyotrophic Lateral Sclerosis | IntechOpen

  https://www.intechopen.com/chapters/45326

  SOD1 is primarily an antioxidant metalloenzyme that catalyzes the conversion of superoxide radical (O2.-) to oxygen (O2) and hydrogen peroxide (H2O2). However, SOD1-linked fALS is most likely not caused by loss of the normal SOD1 activity, but rather by a gain of a toxic function. […] One of the hypotheses for mutant SOD-linked fALS toxicity proposes that an aberrant SOD1 chemistry is responsible for the toxic gain-of-function, which allows small molecules such us peroxynitrite or hydrogen peroxide to produce damaging free radicals. […] Other hypotheses for mutant SOD1 neurotoxicity include inhibition of the proteasome activity, mitochondrial damage, and formation of intracellular aggregates. […] SOD1 aggregation is an early event in ALS and could mediate motor neuron degeneration via sequestration of cellular components, decreasing chaperone activity and the ubiquitin proteasome pathway.

• #16 Pathophysiology of Amyotrophic Lateral Sclerosis | IntechOpen

  https://www.intechopen.com/chapters/45326

  SOD1 is primarily an antioxidant metalloenzyme that catalyzes the conversion of superoxide radical (O2.-) to oxygen (O2) and hydrogen peroxide (H2O2). However, SOD1-linked fALS is most likely not caused by loss of the normal SOD1 activity, but rather by a gain of a toxic function. […] One of the hypotheses for mutant SOD-linked fALS toxicity proposes that an aberrant SOD1 chemistry is responsible for the toxic gain-of-function, which allows small molecules such us peroxynitrite or hydrogen peroxide to produce damaging free radicals. […] Other hypotheses for mutant SOD1 neurotoxicity include inhibition of the proteasome activity, mitochondrial damage, and formation of intracellular aggregates. […] SOD1 aggregation is an early event in ALS and could mediate motor neuron degeneration via sequestration of cellular components, decreasing chaperone activity and the ubiquitin proteasome pathway.

• #17 Pathophysiology of Amyotrophic Lateral Sclerosis | IntechOpen

  https://www.intechopen.com/chapters/45326

  SOD1 is primarily an antioxidant metalloenzyme that catalyzes the conversion of superoxide radical (O2.-) to oxygen (O2) and hydrogen peroxide (H2O2). However, SOD1-linked fALS is most likely not caused by loss of the normal SOD1 activity, but rather by a gain of a toxic function. […] One of the hypotheses for mutant SOD-linked fALS toxicity proposes that an aberrant SOD1 chemistry is responsible for the toxic gain-of-function, which allows small molecules such us peroxynitrite or hydrogen peroxide to produce damaging free radicals. […] Other hypotheses for mutant SOD1 neurotoxicity include inhibition of the proteasome activity, mitochondrial damage, and formation of intracellular aggregates. […] SOD1 aggregation is an early event in ALS and could mediate motor neuron degeneration via sequestration of cellular components, decreasing chaperone activity and the ubiquitin proteasome pathway.

• #18 Pathophysiology of Amyotrophic Lateral Sclerosis | IntechOpen

  https://www.intechopen.com/chapters/45326

  SOD1 is primarily an antioxidant metalloenzyme that catalyzes the conversion of superoxide radical (O2.-) to oxygen (O2) and hydrogen peroxide (H2O2). However, SOD1-linked fALS is most likely not caused by loss of the normal SOD1 activity, but rather by a gain of a toxic function. […] One of the hypotheses for mutant SOD-linked fALS toxicity proposes that an aberrant SOD1 chemistry is responsible for the toxic gain-of-function, which allows small molecules such us peroxynitrite or hydrogen peroxide to produce damaging free radicals. […] Other hypotheses for mutant SOD1 neurotoxicity include inhibition of the proteasome activity, mitochondrial damage, and formation of intracellular aggregates. […] SOD1 aggregation is an early event in ALS and could mediate motor neuron degeneration via sequestration of cellular components, decreasing chaperone activity and the ubiquitin proteasome pathway.

• #19 Pathophysiology of Amyotrophic Lateral Sclerosis | IntechOpen

  https://www.intechopen.com/chapters/45326

  SOD1 is primarily an antioxidant metalloenzyme that catalyzes the conversion of superoxide radical (O2.-) to oxygen (O2) and hydrogen peroxide (H2O2). However, SOD1-linked fALS is most likely not caused by loss of the normal SOD1 activity, but rather by a gain of a toxic function. […] One of the hypotheses for mutant SOD-linked fALS toxicity proposes that an aberrant SOD1 chemistry is responsible for the toxic gain-of-function, which allows small molecules such us peroxynitrite or hydrogen peroxide to produce damaging free radicals. […] Other hypotheses for mutant SOD1 neurotoxicity include inhibition of the proteasome activity, mitochondrial damage, and formation of intracellular aggregates. […] SOD1 aggregation is an early event in ALS and could mediate motor neuron degeneration via sequestration of cellular components, decreasing chaperone activity and the ubiquitin proteasome pathway.

• #20 Amyotrophic lateral sclerosis: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/amyotrophic-lateral-sclerosis/

  In some cases of familial ALS due to mutations in other genes, studies have identified the mechanisms that lead to ALS. […] Some gene mutations lead to a disruption in the development of axons, the specialized extensions of nerve cells (such as motor neurons) that transmit nerve impulses. […] Other mutations lead to a slowing in the transport of materials needed for the proper function of axons in motor neurons, eventually causing the motor neurons to die. […] Additional gene mutations prevent the breakdown of toxic substances, leading to their buildup in nerve cells. […] The accumulation of toxic substances can damage motor neurons and eventually cause cell death. […] The cause of sporadic ALS is largely unknown but probably involves a combination of genetic and environmental factors.

• #21 Pathogenetic mechanisms of amyotrophic lateral sclerosis – Aktualności Neurologiczne – Current Neurology

  https://www.neurologia.com.pl/index.php/issues/2012-vol-12-no-4/pathogenetic-mechanisms-of-amyotrophic-lateral-sclerosis

  Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, resulting in a damage of motor neurons. Pathogenesis of ALS is most probably multifactorial, complex and not entirely elucidated. It may involve such mechanisms as oxidative stress, toxicity of glutamic acid, dysfunction of the mitochondria, stress of endoplasmic reticulum, aggregation of proteins, dysfunction of the cytoskeleton, disturbed axonal transport, role of glial cells, neuroinflammatory process, lactic acid dyscrasia, and genetic factors. An important cause of oxidative stress in ALS are mutations of superoxide dismutase 1 (SOD1) gene leading to altered activity of the enzyme and its enhanced toxicity. Abnormal SOD1 participates in inflammatory response of activated astrocytes and microglia in the spinal cord of ALS patients. Mechanisms of oxidative stress and glutamate toxicity are coupled together. Death of motor neurons occurs as a result if activation of caspases and apoptosis, while mitochondrial dysfunction merely participates in the process. Pathomorphological alterations within the endoplasmic reticulum are present already at an early phase of the disease and indicate that stress within this structure plays an important role in the ALS-related process of neurodegeneration. Another interesting feature of ALS are alterations of cytoskeleton, concerning mainly neurofilaments. According to the hypothesis of lactic acid dyscrasia, dysregulation of myoneuronal lactic acid channel results in cellular stress, toxicity and progressive degeneration. An important role in the pathogenesis of ALS may be also played by genetic mutations of proteins other than SOD1.

• #22

  https://journals.lww.com/annalsofian/fulltext/2011/14040/altered_rna_metabolism_and_amyotrophic_lateral.3.aspx

  Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease in adults. […] The biologic basis of the disease is unknown. However, ALS research has taken a dramatic turn over the last 3 years. Landmark discoveries of mutations in the transactive response DNA-binding protein (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS) as causative of ALS and demonstration that abnormal aggregation of these proteins is the proximate cause of motor neuron loss in familial and sporadic ALS have initiated a paradigm shift in understanding the pathogenic mechanism of this disease. […] A major shift in our understanding of ALS pathogenesis occurred in 2006, with the identification of a 43-kDa transactive response (TAR) DNA-binding protein (TDP-43) as a key pathological substrate of cytosolic inclusions in sALS and frontotemporal lobe degeneration with ubiquitin inclusions (FTLD-U).

• #23

  https://journals.lww.com/annalsofian/fulltext/2011/14040/altered_rna_metabolism_and_amyotrophic_lateral.3.aspx

  The identification of TDP-43 mutations was in tandem followed by the discovery of mutations in another RNA/DNA-binding protein FUS/TLS (fused in sarcoma and translocated in liposarcoma) in 2009, as a primary cause of fALS. […] Taken together, the emerging concept that ALS is a RNA-processing disorder is taking a tangible shape. […] This review summarizes the literature pertaining to recently identified TDP-43 and FUS/TLS mutations as RNA-processing errors in ALS and its implication in understanding the pathogenic mechanism of the disease and possible future therapies. […] The mounting evidence over the last 3 years strongly implicates TDP-43 and FUS/TLS in motor neuron degeneration in ALS through errors in multiple steps of RNA processing. […] The major question underlying ALS pathogenesis that needs resolution: Is ALS from TDP-43 or FUS/TLS mutation caused by the loss of normal function or gain of one or more toxic properties, or both?

• #24 Amyotrophic Lateral Sclerosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK556151/

  Over 120 genes have been implicated in ALS. A prevailing thought is that the accumulation of abnormal proteins due to aberrant RNA processing is involved in the development of ALS. […] The accumulation of TDP-43 is present in most cases of sporadic ALS, FTD, ALS-FTD, and some cases of familial ALS. […] The interplay of epigenetics (ie, a modification of gene expression rather than a modification of the genetic code itself), a trigger factor (risk variables described above), a propagating channel (oxidative stress, excitotoxicity, defective RNA processing, intraneuronal protein aggregates, mitochondrial dysfunction, neuroinflammation, or protein misfolding) and final clinical manifestations have also been advocated.

• #25 Mechanism discovered for how amyotrophic lateral sclerosis mutations damage nerve function – St. Jude Children’s Research Hospital

  https://www.stjude.org/media-resources/news-releases/2014-medicine-science-news/mechanism-discovered-for-how-amyotrophic-lateral-sclerosis-mutations-damage-nerve-function.html

  St. Jude Childrens Research Hospital scientists led a study showing that mutations in a gene responsible for amyotrophic lateral sclerosis (ALS) disrupt the RNA transport system in nerve cells. […] This study showed for the first time that the mutations disrupt efficient movement within nerve cells of RNA molecules. […] Working in motor neurons derived from patients with ALS, researchers demonstrated that each of three different TDP-43 mutations impaired delivery of RNA molecules to their final destination near the junction where a nerve and its target muscle meet. […] The results also provide insight into how problems in RNA metabolism, including disturbances in RNA regulation and functioning, lead to ALS and other neurodegenerative diseases. […] This study provides a more refined understanding of how ALS-causing mutations impair RNA metabolism so we know what needs fixing therapeutically.

• #26 Mechanism that causes ALS nerve destruction unveiled for first time

  https://www.drugtargetreview.com/news/100292/mechanism-that-causes-als-nerve-destruction-unveiled-for-first-time/

  The dysfunction of mitochondria in nerve terminals leads to neuromuscular junction disruption and the death of motor neurons. […] In our current study, we focused on a pathological change in TDP-43 protein that takes place in these axons and at neuromuscular junctions, Perlson continued. […] We showed that in ALS this protein exits the nucleus and accumulates throughout the entire cell and particularly in the neuromuscular junction. […] The team discovered that the accumulations formed by the TDP-43 protein in neuromuscular junctions trap RNA molecules and prevent the synthesis of proteins to mitochondrial function. […] The condensation of TDP-43 protein resulted in a severe energy depletion, prevented mitochondrial repair, and consequently led to the disruption of these junctions, the degeneration of the entire extension cable and to the death of motor neurons in the spinal cord.

• #27 Mechanism that causes ALS nerve destruction unveiled for first time

  https://www.drugtargetreview.com/news/100292/mechanism-that-causes-als-nerve-destruction-unveiled-for-first-time/

  The dysfunction of mitochondria in nerve terminals leads to neuromuscular junction disruption and the death of motor neurons. […] In our current study, we focused on a pathological change in TDP-43 protein that takes place in these axons and at neuromuscular junctions, Perlson continued. […] We showed that in ALS this protein exits the nucleus and accumulates throughout the entire cell and particularly in the neuromuscular junction. […] The team discovered that the accumulations formed by the TDP-43 protein in neuromuscular junctions trap RNA molecules and prevent the synthesis of proteins to mitochondrial function. […] The condensation of TDP-43 protein resulted in a severe energy depletion, prevented mitochondrial repair, and consequently led to the disruption of these junctions, the degeneration of the entire extension cable and to the death of motor neurons in the spinal cord.

• #28 Why do motor neurons degenerate? Actualisation in the pathogenesis of amyotrophic lateral sclerosis | Neurología (English Edition)

  https://www.elsevier.es/en-revista-neurologia-english-edition-495-articulo-why-do-motor-neurons-degenerate-S2173580817301633

  Although ALS involves multiple pathogenic mechanisms which are yet to be determined, a number of genetic factors and alterations in the main cellular pathways have been characterised and associated with disease onset. […] A large number of proteins which have been linked to ALS are directly or indirectly involved in nucleic acid processing. […] Subsequent identification of mutations in TDP-43 and FUS confirmed that aberrant RNA metabolism may contribute to the pathogenesis of ALS. […] The mechanisms by which TDP-43 mutations lead to the development of ALS are yet to be determined. […] Although the exact mechanisms of FUS cytotoxicity are yet to be understood, it has been suggested that gain- and loss-of-function phenomena may coexist, as occurs with TDP-43. […] The pathogenic mechanism by which an excessive number of repeats is associated with disease development is yet to be determined.

• #29 Why do motor neurons degenerate? Actualisation in the pathogenesis of amyotrophic lateral sclerosis | Neurología (English Edition)

  https://www.elsevier.es/en-revista-neurologia-english-edition-495-articulo-why-do-motor-neurons-degenerate-S2173580817301633

  Although ALS involves multiple pathogenic mechanisms which are yet to be determined, a number of genetic factors and alterations in the main cellular pathways have been characterised and associated with disease onset. […] A large number of proteins which have been linked to ALS are directly or indirectly involved in nucleic acid processing. […] Subsequent identification of mutations in TDP-43 and FUS confirmed that aberrant RNA metabolism may contribute to the pathogenesis of ALS. […] The mechanisms by which TDP-43 mutations lead to the development of ALS are yet to be determined. […] Although the exact mechanisms of FUS cytotoxicity are yet to be understood, it has been suggested that gain- and loss-of-function phenomena may coexist, as occurs with TDP-43. […] The pathogenic mechanism by which an excessive number of repeats is associated with disease development is yet to be determined.

• #30 Why do motor neurons degenerate? Actualisation in the pathogenesis of amyotrophic lateral sclerosis | Neurología (English Edition)

  https://www.elsevier.es/en-revista-neurologia-english-edition-495-articulo-why-do-motor-neurons-degenerate-S2173580817301633

  Although ALS involves multiple pathogenic mechanisms which are yet to be determined, a number of genetic factors and alterations in the main cellular pathways have been characterised and associated with disease onset. […] A large number of proteins which have been linked to ALS are directly or indirectly involved in nucleic acid processing. […] Subsequent identification of mutations in TDP-43 and FUS confirmed that aberrant RNA metabolism may contribute to the pathogenesis of ALS. […] The mechanisms by which TDP-43 mutations lead to the development of ALS are yet to be determined. […] Although the exact mechanisms of FUS cytotoxicity are yet to be understood, it has been suggested that gain- and loss-of-function phenomena may coexist, as occurs with TDP-43. […] The pathogenic mechanism by which an excessive number of repeats is associated with disease development is yet to be determined.

• #31 Pathophysiology of Amyotrophic Lateral Sclerosis | IntechOpen

  https://www.intechopen.com/chapters/45326

  Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by death of pyramidal neurons in the motor cortex (upper motor neurons) and motor neurons in the brain stem and central spinal cord (lower motor neurons). This results in muscle weakness, progressive motor disability, and finally death by respiratory failure or an associated infection (Shook and Pioro, 2009). […] In the last few years, there had been an explosion of genetic studies associating ALS with several genetic mutations in genes codifying for different proteins: Cu/Zn superoxide dismutase, (SOD1), transactive response binding protein 43 (TARDBP), fused in sarcoma (FUS), and valosin containing protein (VCP). Most recently, a genetic defect was identified with an expansion of the noncoding GGGGCC hexanucleotide repeat in the chromosome 9, open reading frame 72 (C9ORF72), associated with ALS with and without frontotemporal dementia (Boeve et al., 2012).

• #32 The pathophysiology of amyotrophic lateral sclerosis (ALS) and the role of C9orf72

  https://www.linkedin.com/pulse/pathophysiology-amyotrophic-lateral-sclerosis-als-role-hoffman

  Morphological and ultrastructural deformities of mitochondria have been found in autopsies of patients with ALS. […] The correlation between ALS and pesticide exposure has been investigated in several studies. […] The C9orf72 gene is so special, because it lies in an intronic region and is transcribed, although normally only exons are transcribed, not introns. […] ALS has been related to the loss-of-function of the C9orf72 gene, gain-of-function of the C9orf72 gene via RNA repeats, gain-of-function via DPR protein, and finally the formation of G-quadruplexes. […] The manner of action in ALS is by way of sequestration of essential RNA-binding proteins into aggregates of repeat containing RNA foci, in the nucleus of the affected cell. […] The final genetical mechanism in ALS involves G-quadruplexes. The C9orf72 hexanucleotide repeat expansions DNA and RNA set up the formation of G-quadruplexes.

• #33 Why do motor neurons degenerate? Actualisation in the pathogenesis of amyotrophic lateral sclerosis | Neurología (English Edition)

  https://www.elsevier.es/en-revista-neurologia-english-edition-495-articulo-why-do-motor-neurons-degenerate-S2173580817301633

  Some studies including patients with this expansion have shown that their levels of C9ORF72 mRNA were up to 50% lower, which suggests that the mutant allele is probably unable to produce mature RNA; this would be linked to the hypothesis of a loss-of-function process. […] In addition to the damage it causes directly, oxidative stress promotes other pathogenic mechanisms which contribute to neuronal alterations, including excitotoxicity, protein aggregation, ER stress response, and mitochondrial dysfunction, and it also affects the interaction between motor neurons and the neuronal microenvironment. […] Although motor neuron degeneration and loss is the main finding in patients with ALS, the condition has also been associated with activation of a neuroinflammatory response. […] This inflammatory response contributes to the progressive degeneration and phenotypic alteration of motor neurons, starting with the first manifestations of the disease.

• #34 The pathophysiology of amyotrophic lateral sclerosis (ALS) and the role of C9orf72

  https://www.linkedin.com/pulse/pathophysiology-amyotrophic-lateral-sclerosis-als-role-hoffman

  Morphological and ultrastructural deformities of mitochondria have been found in autopsies of patients with ALS. […] The correlation between ALS and pesticide exposure has been investigated in several studies. […] The C9orf72 gene is so special, because it lies in an intronic region and is transcribed, although normally only exons are transcribed, not introns. […] ALS has been related to the loss-of-function of the C9orf72 gene, gain-of-function of the C9orf72 gene via RNA repeats, gain-of-function via DPR protein, and finally the formation of G-quadruplexes. […] The manner of action in ALS is by way of sequestration of essential RNA-binding proteins into aggregates of repeat containing RNA foci, in the nucleus of the affected cell. […] The final genetical mechanism in ALS involves G-quadruplexes. The C9orf72 hexanucleotide repeat expansions DNA and RNA set up the formation of G-quadruplexes.

• #35 The pathophysiology of amyotrophic lateral sclerosis (ALS) and the role of C9orf72

  https://www.linkedin.com/pulse/pathophysiology-amyotrophic-lateral-sclerosis-als-role-hoffman

  Morphological and ultrastructural deformities of mitochondria have been found in autopsies of patients with ALS. […] The correlation between ALS and pesticide exposure has been investigated in several studies. […] The C9orf72 gene is so special, because it lies in an intronic region and is transcribed, although normally only exons are transcribed, not introns. […] ALS has been related to the loss-of-function of the C9orf72 gene, gain-of-function of the C9orf72 gene via RNA repeats, gain-of-function via DPR protein, and finally the formation of G-quadruplexes. […] The manner of action in ALS is by way of sequestration of essential RNA-binding proteins into aggregates of repeat containing RNA foci, in the nucleus of the affected cell. […] The final genetical mechanism in ALS involves G-quadruplexes. The C9orf72 hexanucleotide repeat expansions DNA and RNA set up the formation of G-quadruplexes.

• #36 The pathophysiology of amyotrophic lateral sclerosis (ALS) and the role of C9orf72

  https://www.linkedin.com/pulse/pathophysiology-amyotrophic-lateral-sclerosis-als-role-hoffman

  Morphological and ultrastructural deformities of mitochondria have been found in autopsies of patients with ALS. […] The correlation between ALS and pesticide exposure has been investigated in several studies. […] The C9orf72 gene is so special, because it lies in an intronic region and is transcribed, although normally only exons are transcribed, not introns. […] ALS has been related to the loss-of-function of the C9orf72 gene, gain-of-function of the C9orf72 gene via RNA repeats, gain-of-function via DPR protein, and finally the formation of G-quadruplexes. […] The manner of action in ALS is by way of sequestration of essential RNA-binding proteins into aggregates of repeat containing RNA foci, in the nucleus of the affected cell. […] The final genetical mechanism in ALS involves G-quadruplexes. The C9orf72 hexanucleotide repeat expansions DNA and RNA set up the formation of G-quadruplexes.

• #37 Amyotrophic Lateral Sclerosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1170097-overview

  Pathways that lead to cell death in ALS may be mediated by the following: oxidative damage, mitochondrial dysfunction, caspase-mediated cell death (apoptosis), defects in axonal transport, abnormal growth factor expression, glial cell pathology, glutamate excitotoxicity, aggregation of abnormal proteins. […] The findings below have placed derangements of RNA metabolism at the core of current thinking with regard to the pathophysiology of most types of ALS. […] Making the distinction between the pathogenesis and pathophysiology of ALS matters because the mechanisms underlying each of these stages are probably different. […] The multistep hypothesis for disease pathogenesis provides a fairly good idea regarding how and where ALS is initiated. […] In summary, our current understanding of ALS pathogenesis is sufficiently advanced, that it is time to retire the adage the cause of ALS is unknown. It is more correct to say that we have a fairly good understanding of how ALS is initiated and how it spreads, new and more specific information is emerging every year, and that this information has led and is leading to clinical trials focusing more directly on the processes involved early in the course of the disease.

• #38

  https://journals.lww.com/annalsofian/fulltext/2011/14040/altered_rna_metabolism_and_amyotrophic_lateral.3.aspx

  The identification of TDP-43 mutations was in tandem followed by the discovery of mutations in another RNA/DNA-binding protein FUS/TLS (fused in sarcoma and translocated in liposarcoma) in 2009, as a primary cause of fALS. […] Taken together, the emerging concept that ALS is a RNA-processing disorder is taking a tangible shape. […] This review summarizes the literature pertaining to recently identified TDP-43 and FUS/TLS mutations as RNA-processing errors in ALS and its implication in understanding the pathogenic mechanism of the disease and possible future therapies. […] The mounting evidence over the last 3 years strongly implicates TDP-43 and FUS/TLS in motor neuron degeneration in ALS through errors in multiple steps of RNA processing. […] The major question underlying ALS pathogenesis that needs resolution: Is ALS from TDP-43 or FUS/TLS mutation caused by the loss of normal function or gain of one or more toxic properties, or both?

• #39 Mechanism discovered for how amyotrophic lateral sclerosis mutations damage nerve function – St. Jude Children’s Research Hospital

  https://www.stjude.org/media-resources/news-releases/2014-medicine-science-news/mechanism-discovered-for-how-amyotrophic-lateral-sclerosis-mutations-damage-nerve-function.html

  St. Jude Childrens Research Hospital scientists led a study showing that mutations in a gene responsible for amyotrophic lateral sclerosis (ALS) disrupt the RNA transport system in nerve cells. […] This study showed for the first time that the mutations disrupt efficient movement within nerve cells of RNA molecules. […] Working in motor neurons derived from patients with ALS, researchers demonstrated that each of three different TDP-43 mutations impaired delivery of RNA molecules to their final destination near the junction where a nerve and its target muscle meet. […] The results also provide insight into how problems in RNA metabolism, including disturbances in RNA regulation and functioning, lead to ALS and other neurodegenerative diseases. […] This study provides a more refined understanding of how ALS-causing mutations impair RNA metabolism so we know what needs fixing therapeutically.

• #40 Mechanism discovered for how amyotrophic lateral sclerosis mutations damage nerve function – St. Jude Children’s Research Hospital

  https://www.stjude.org/media-resources/news-releases/2014-medicine-science-news/mechanism-discovered-for-how-amyotrophic-lateral-sclerosis-mutations-damage-nerve-function.html

  Researchers demonstrated that TDP-43 is part of a molecule called an RNA transport granule. […] In human motor neurons growing in the laboratory, investigators found that transport granules with mutant TDP-43 were more likely than granules with unaltered TDP-43 to stall en route to the nerve ending and sometimes reverse direction. […] Evidence from mice suggests TDP-43 mutations selectively rather than globally disrupt movement in nerve cells. […] We know neurodegenerative disorders, including Parkinsons and Alzheimers diseases, seem to share a common mechanism.

• #41 Pathophysiology of Amyotrophic Lateral Sclerosis | IntechOpen

  https://www.intechopen.com/chapters/45326

  Also, SOD1 mutations seem to disrupt RNA processing in the cells. […] A dominant hypothesis of ALS pathogenesis is glutamate excitotoxicity. […] In addition, defects in glutamate transport leading to elevated glutamate levels have been reported in mSOD1 mice and significant number of patients with sALS (Dunlop et al., Lin et al., Rothstein et al.,). […] The mechanism of glutamate neurotoxicity remains elusive. […] Excessive glutamate levels lead to activation of glutamate ionotropic AMPA receptors in neurons and glial cells. […] Mitochondrial malfunction is an important hypothesis in ALS pathogenesis (Bruijn et al., 2004; Manfredi et al., 2005). […] Indeed, mitochondria morphological and ultrastructural changes as well as bioenergetic malfunction have been reported in ALS. […] Abnormalities in mitochondrial calcium homeostasis were reported in ALS patients and in mutant SOD1 animals (Kruman et al., 1999; Carri et al., 1997; Reiner et al, 1995; Jaiswal et al., 2009).

• #42

  https://journals.lww.com/nrronline/fulltext/2024/05000/pathological_mechanisms_of_amyotrophic_lateral.32.aspx

  At present, ALS pathogenesis is still unclear, as it involves a very large number of cellular processes, so it is still difficult to determine which of these are pathogenic factors. […] Although the specific pathogenic mechanisms of ALS remain unresolved after many years of research, the pathophysiological mechanisms of the disease may be due to a combination of mechanisms mediated via complicated interactions among molecular and genetic pathways rather than a single factor. […] A variety of disease mechanisms have been suggested, which include glutamate excitotoxicity, free radical-mediated oxidative stress, structural and functional abnormalities in mitochondria, proteostasis, abnormal RNA metabolism, nucleocytoplasmic transport detects, impaired DNA damage and DNA repair, neuroinflammation, oligodendrocyte dysfunction, and axonal transport defects.

• #43 Advances and challenges in understanding the multifaceted pathogenesis of amyotrophic lateral sclerosis

  https://smw.ch/index.php/smw/article/download/1990/2861?inline=1

  Several cytotoxic mechanisms have been described for C9ORF72 hexanucleotide repeat expansions and their relative contribution to ALS pathogenesis is currently under investigation. […] The physiological function of a protein is often linked to a unique structure and stable three-dimensional conformation, as a result of a normal folding pathway. Some proteins can gain toxic properties upon a disturbance of their structure that can stably exist and be transferred to homologous proteins if their structure allows this pathological conformation. This mechanism underlies the pathogenesis of prion diseases, and is suggested to contribute to the progression of many neurodegenerative diseases, such as Alzheimers and Parkinsons diseases. […] The aggregation properties of TDP-43 and FUS are associated with their physiological role in the formation of stress granules. […] All above mechanisms may contribute to C9ORF72 disease and the spreading of TDP-43 pathology in patients with hexanucleotide repeat expansions. […] In conclusion, ALS is complex and heterogeneous disease that is caused by many, seemingly diverse, upstream events.

• #44 Pathogenetic mechanisms of amyotrophic lateral sclerosis – Aktualności Neurologiczne – Current Neurology

  https://www.neurologia.com.pl/index.php/issues/2012-vol-12-no-4/pathogenetic-mechanisms-of-amyotrophic-lateral-sclerosis

  Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, resulting in a damage of motor neurons. Pathogenesis of ALS is most probably multifactorial, complex and not entirely elucidated. It may involve such mechanisms as oxidative stress, toxicity of glutamic acid, dysfunction of the mitochondria, stress of endoplasmic reticulum, aggregation of proteins, dysfunction of the cytoskeleton, disturbed axonal transport, role of glial cells, neuroinflammatory process, lactic acid dyscrasia, and genetic factors. An important cause of oxidative stress in ALS are mutations of superoxide dismutase 1 (SOD1) gene leading to altered activity of the enzyme and its enhanced toxicity. Abnormal SOD1 participates in inflammatory response of activated astrocytes and microglia in the spinal cord of ALS patients. Mechanisms of oxidative stress and glutamate toxicity are coupled together. Death of motor neurons occurs as a result if activation of caspases and apoptosis, while mitochondrial dysfunction merely participates in the process. Pathomorphological alterations within the endoplasmic reticulum are present already at an early phase of the disease and indicate that stress within this structure plays an important role in the ALS-related process of neurodegeneration. Another interesting feature of ALS are alterations of cytoskeleton, concerning mainly neurofilaments. According to the hypothesis of lactic acid dyscrasia, dysregulation of myoneuronal lactic acid channel results in cellular stress, toxicity and progressive degeneration. An important role in the pathogenesis of ALS may be also played by genetic mutations of proteins other than SOD1.

• #45 Amyotrophic Lateral Sclerosis: Molecular Mechanisms, Biomarkers, and Therapeutic Strategies

  https://www.mdpi.com/2076-3921/10/7/1012

  Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with the progressive loss of motor neurons, leading to a fatal paralysis. […] Despite decades of research, the pathogenesis of ALS is still unelucidated. […] We review the recent progress of ALS pathogenesis, biomarkers, and treatment strategies, mainly discuss the roles of immune disorders, redox imbalance, autophagy dysfunction, and disordered iron homeostasis in the pathogenesis of ALS. […] In the past few decades, a breakthrough has been made in understanding the pathogenesis of ALS. Immune disorders, redox imbalance, autophagy dysfunction, and disordered iron homeostasis are important factors involved in the pathogenesis of ALS. […] The immune system is an important part involved in the pathogenesis of ALS. […] Increasing evidence highlights the importance of redox imbalance in the pathogenesis of ALS.

• #46

  https://omim.org/entry/105400

  ALS is a genetically heterogeneous disorder, with several causative genes and mapped loci. […] Rothstein et al. (1992) found in in vitro studies that synaptosomes in neural tissue obtained from 13 ALS patients showed a marked decrease in the maximal velocity of transport for high-affinity glutamate uptake in spinal cord, motor cortex, and somatosensory cortex compared to controls. […] Liu et al. (1998) demonstrated increased free radical production in the spinal cord but not the brain of transgenic mice expressing mutant human SOD1 (G93A; 147450.0008), which preceded the degeneration of motor neurons. […] Li et al. (2000) demonstrated an 81.5% elevation of caspase-1 (CASP1; 147678) activity in the spinal cord of humans with ALS when compared with normal controls, and, using an animal model, suggested that caspases play an instrumental role in the neurodegenerative processing of ALS.

• #47 Amyotrophic Lateral Sclerosis Signaling | GeneGlobe

  https://geneglobe.qiagen.com/us/knowledge/pathways/amyotrophic-lateral-sclerosis-signaling

  Amyotrophic lateral sclerosis (ALS, also called Maladie the Charcot or Lou Gehrig’s disease) is a progressive, usually fatal paralytic disorder caused by the degeneration of motor neurons. The cause of ALS is currently unknown, but appears to involve different mechanisms:1. Oxidative damage. Approximately 20% of all familial cases is linked to mutations in the gene for the cytosolic free radical-scavenging enzyme superoxide dismutase-1 (SOD1). Mutant SOD1 catalyses aberrant biochemical reactions, resulting in the production of potentially damaging reactive oxygen species, such as superoxide anion, hydroxyl radical, hydrogen peroxide and peroxynitrite. The neuronal oxidative damage seen in ALS could be generated by hydroxyl radical (Peroxidase hypothesis) and/or peroxynitrite (Peroxynitrie hypothesis).2. Glutamate-induced excitotoxicity. Neuronal membrane depolarization after activation of glutamate receptors activates voltage-dependent Ca2+ channels, which allows Ca2+ influx into the cell. Glutamate activity is regulated by receptor inactivation and glutamate reuptake by the transporter protein SLC1A2. It has been shown that this transporter level is reduced in motor cortex and spinal cord of ALS patients. Moreover, oxidative damage by ROS has been suggested as another possible mechanism by which the glutamate transporter SLC1A2 could be inactivated. Thus, this loss of glutamate transporter could lead to an excessive activation of glutamate receptors and a prolonged Ca2+ entry, which could cause excitotoxic degeneration of motor neurons.3. Neurofilament (NF) inclusion. A pathological hallmark of ALS is the presence of abnormal neurofilament inclusions in the perikaryon and axon of motor neurons. Extensive reduction in NF-L level has been demonstrated in degenerating motor neurons of ALS patients. This protein is required for proper neurofilament assembly and transport, therefore a lack of NF-L can provoke accumulation of NF-M and NF-H, which can lead to perikaryal neurofilament inclusions. Peripherin is another type of intermediate filament protein that has been identified in motor neuron inclusions in ALS patients. Peripherin heterodimerizes with each of the NF subunits to establish an intermediate filament network. However, because of the reduced level of NF-L, the interaction between peripherin and NF-M and NF-H results in disorganized network, triggering the formation of axonal peripherin inclusions.4. Impaired mitochondrial function. Mitochondrial degeneration, manifested by mitochondrial vacuolization, has been reported in ALS motor neurons. Mutant SOD1, upregulated proteins (Bax), downregulated proteins (Bcl-2, Bcl-xl) present in motor neurons of ALS patients initiate cytochrome c release from the mitochondria into the cytoplasm, which activates caspase-3, leading to motor neuron apoptosis. […] ALS pathogenesis involves multiple cascades of events including oxidative damage, excitotoxicity, aberrant protein aggregation, mitochondrial defects, and caspase activation, leading to motor neuron death in ALS patients.

• #48 Amyotrophic Lateral Sclerosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1170097-overview

  Pathways that lead to cell death in ALS may be mediated by the following: oxidative damage, mitochondrial dysfunction, caspase-mediated cell death (apoptosis), defects in axonal transport, abnormal growth factor expression, glial cell pathology, glutamate excitotoxicity, aggregation of abnormal proteins. […] The findings below have placed derangements of RNA metabolism at the core of current thinking with regard to the pathophysiology of most types of ALS. […] Making the distinction between the pathogenesis and pathophysiology of ALS matters because the mechanisms underlying each of these stages are probably different. […] The multistep hypothesis for disease pathogenesis provides a fairly good idea regarding how and where ALS is initiated. […] In summary, our current understanding of ALS pathogenesis is sufficiently advanced, that it is time to retire the adage the cause of ALS is unknown. It is more correct to say that we have a fairly good understanding of how ALS is initiated and how it spreads, new and more specific information is emerging every year, and that this information has led and is leading to clinical trials focusing more directly on the processes involved early in the course of the disease.

• #49 VectorY Therapeutics to Present Preclinical Data on Novel ALS Therapeutic Strategy at Target ALS Conference in Boston

  https://www.businesswire.com/news/home/20250507576427/en/VectorY-Therapeutics-to-Present-Preclinical-Data-on-Novel-ALS-Therapeutic-Strategy-at-Target-ALS-Conference-in-Boston

  ~ New data show AAV-delivered antibody fragments targeting oxidized phosphatidylcholines (PC-OxPL), a species of oxidized phospholipids, thereby neutralizing TDP-43 pathology and motor neuron toxicity in ALS models ~ […] ~ Underscores potential of VTx-001 to act on upstream drivers of ALS ~ […] “These findings support our hypothesis that PC-OxPL molecules are a key mediator of ALS pathology, acting upstream of TDP-43 proteinopathy and motor neuron toxicity,” said Sander van Deventer, M.D., Ph.D., president of research and development at VectorY. […] The data underscore the potential of VTx-001 to neutralize upstream pathological drivers in amyotrophic lateral sclerosis (ALS), including oxidized phosphatidylcholines (PC-OxPL), which have been implicated in triggering ALS hallmark TDP-43 proteinopathy and motor neuron degeneration.

• #50 VectorY Therapeutics to Present Preclinical Data on Novel ALS Therapeutic Strategy at Target ALS Conference in Boston – BioSpace

  https://www.biospace.com/press-releases/vectory-therapeutics-to-present-preclinical-data-on-novel-als-therapeutic-strategy-at-target-als-conference-in-boston

  New data show AAV-delivered antibody fragments targeting oxidized phosphatidylcholines (PC-OxPL), thereby neutralizing TDP-43 pathology and motor neuron toxicity in ALS models […] The data underscore the potential of VTx-001 to neutralize upstream pathological drivers in amyotrophic lateral sclerosis (ALS), including oxidized phosphatidylcholines (PC-OxPL), which have been implicated in triggering ALS hallmark TDP-43 proteinopathy and motor neuron degeneration. […] These findings support our hypothesis that PC-OxPL molecules are a key mediator of ALS pathology, acting upstream of TDP-43 proteinopathy and motor neuron toxicity.

• #51 Pathophysiology of Amyotrophic Lateral Sclerosis — Firstclass

  https://www.firstclassmed.com/articles/2023/pathophysiology-of-als

  Understand that the genetic mutations set the stage for the other pathogenetic processes to take place. Without them, the disease would not occur. Of the subsequent processes, research has shown that excitotoxicity is the most prevalent pathogenetic mechanism which leads to motor neurone damage in ALS. […] Excitotoxicity is the dominant hypothesis of ALS pathogenesis. Glutamate is the major excitatory neurotransmitter in mammalian CNS but in high concentrations, glutamate is toxic to neurones. […] The motor neurones die through Wallerian degeneration. The death of one neurone leads to axonal degeneration and death. […] When the denervation exceeds the renervation process, clinical features manifest themselves. Progressive denervation leads to atrophy of the whole muscle causing amyotrophy. […] As the damage extends to the cortical motor neurones, there is thinning of the corticospinal tracts. These tracts travel the lateral and anterior part of the spinal cord. Progressive loss of fibers leads to gliosis which makes the tracts firm which appears as lateral sclerosis on autopsy.

• #52 ALS Pathogenesis and Therapeutic Approaches: The Role of Mesenchymal Stem Cells and Extracellular Vesicles

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5359305/

  The pathophysiological mechanism of the disease appears to be multifactorial and several mechanisms contribute to neurodegeneration. An increase of the neurotransmitter glutamate in the synaptic cleft (glutamate excitotoxicity), due to the impairment of its uptake by astrocytes, leads to an increased influx of Ca2+ ions in the motoneurons. […] Mitochondrial damage is a common feature of many neurodegenerative diseases. Mitochondria are the most important organelles for energy production, cellular respiration and calcium homeostasis. […] The majority of SOD1 mutations are associated with an autosomal dominant form of the disease (ALS1) and G93A, alanine at codon 4 changed to valine (A4V), H46R and D90A are the most commonly reported ALS mutations. […] Gene mutations can cause a dominant gain of function, resulting in an increase of SOD1 activity, with an excessive production of H2O2, or in a dominant loss of function with a decrease in enzyme activity which results in insufficient degradation of ROS.

• #53 Pathophysiology of Amyotrophic Lateral Sclerosis | IntechOpen

  https://www.intechopen.com/chapters/45326

  Also, SOD1 mutations seem to disrupt RNA processing in the cells. […] A dominant hypothesis of ALS pathogenesis is glutamate excitotoxicity. […] In addition, defects in glutamate transport leading to elevated glutamate levels have been reported in mSOD1 mice and significant number of patients with sALS (Dunlop et al., Lin et al., Rothstein et al.,). […] The mechanism of glutamate neurotoxicity remains elusive. […] Excessive glutamate levels lead to activation of glutamate ionotropic AMPA receptors in neurons and glial cells. […] Mitochondrial malfunction is an important hypothesis in ALS pathogenesis (Bruijn et al., 2004; Manfredi et al., 2005). […] Indeed, mitochondria morphological and ultrastructural changes as well as bioenergetic malfunction have been reported in ALS. […] Abnormalities in mitochondrial calcium homeostasis were reported in ALS patients and in mutant SOD1 animals (Kruman et al., 1999; Carri et al., 1997; Reiner et al, 1995; Jaiswal et al., 2009).

• #54 ALS Pathogenesis and Therapeutic Approaches: The Role of Mesenchymal Stem Cells and Extracellular Vesicles

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5359305/

  The pathophysiological mechanism of the disease appears to be multifactorial and several mechanisms contribute to neurodegeneration. An increase of the neurotransmitter glutamate in the synaptic cleft (glutamate excitotoxicity), due to the impairment of its uptake by astrocytes, leads to an increased influx of Ca2+ ions in the motoneurons. […] Mitochondrial damage is a common feature of many neurodegenerative diseases. Mitochondria are the most important organelles for energy production, cellular respiration and calcium homeostasis. […] The majority of SOD1 mutations are associated with an autosomal dominant form of the disease (ALS1) and G93A, alanine at codon 4 changed to valine (A4V), H46R and D90A are the most commonly reported ALS mutations. […] Gene mutations can cause a dominant gain of function, resulting in an increase of SOD1 activity, with an excessive production of H2O2, or in a dominant loss of function with a decrease in enzyme activity which results in insufficient degradation of ROS.

• #55 Amyotrophic Lateral Sclerosis Signaling | GeneGlobe

  https://geneglobe.qiagen.com/us/knowledge/pathways/amyotrophic-lateral-sclerosis-signaling

  Amyotrophic lateral sclerosis (ALS, also called Maladie the Charcot or Lou Gehrig’s disease) is a progressive, usually fatal paralytic disorder caused by the degeneration of motor neurons. The cause of ALS is currently unknown, but appears to involve different mechanisms:1. Oxidative damage. Approximately 20% of all familial cases is linked to mutations in the gene for the cytosolic free radical-scavenging enzyme superoxide dismutase-1 (SOD1). Mutant SOD1 catalyses aberrant biochemical reactions, resulting in the production of potentially damaging reactive oxygen species, such as superoxide anion, hydroxyl radical, hydrogen peroxide and peroxynitrite. The neuronal oxidative damage seen in ALS could be generated by hydroxyl radical (Peroxidase hypothesis) and/or peroxynitrite (Peroxynitrie hypothesis).2. Glutamate-induced excitotoxicity. Neuronal membrane depolarization after activation of glutamate receptors activates voltage-dependent Ca2+ channels, which allows Ca2+ influx into the cell. Glutamate activity is regulated by receptor inactivation and glutamate reuptake by the transporter protein SLC1A2. It has been shown that this transporter level is reduced in motor cortex and spinal cord of ALS patients. Moreover, oxidative damage by ROS has been suggested as another possible mechanism by which the glutamate transporter SLC1A2 could be inactivated. Thus, this loss of glutamate transporter could lead to an excessive activation of glutamate receptors and a prolonged Ca2+ entry, which could cause excitotoxic degeneration of motor neurons.3. Neurofilament (NF) inclusion. A pathological hallmark of ALS is the presence of abnormal neurofilament inclusions in the perikaryon and axon of motor neurons. Extensive reduction in NF-L level has been demonstrated in degenerating motor neurons of ALS patients. This protein is required for proper neurofilament assembly and transport, therefore a lack of NF-L can provoke accumulation of NF-M and NF-H, which can lead to perikaryal neurofilament inclusions. Peripherin is another type of intermediate filament protein that has been identified in motor neuron inclusions in ALS patients. Peripherin heterodimerizes with each of the NF subunits to establish an intermediate filament network. However, because of the reduced level of NF-L, the interaction between peripherin and NF-M and NF-H results in disorganized network, triggering the formation of axonal peripherin inclusions.4. Impaired mitochondrial function. Mitochondrial degeneration, manifested by mitochondrial vacuolization, has been reported in ALS motor neurons. Mutant SOD1, upregulated proteins (Bax), downregulated proteins (Bcl-2, Bcl-xl) present in motor neurons of ALS patients initiate cytochrome c release from the mitochondria into the cytoplasm, which activates caspase-3, leading to motor neuron apoptosis. […] ALS pathogenesis involves multiple cascades of events including oxidative damage, excitotoxicity, aberrant protein aggregation, mitochondrial defects, and caspase activation, leading to motor neuron death in ALS patients.

• #56

  https://journals.lww.com/nrronline/fulltext/2024/05000/pathological_mechanisms_of_amyotrophic_lateral.32.aspx

  Neuroinflammation has been suggested to play a key role within ALS disease onset and progression. […] Activated microglia can activate astrocyte neurotoxicity by secreting inflammatory factors. […] Impaired proteostasis: Aggregated pathological proteins can accumulate in the cytoplasm in large quantities. […] Oxidative stress has been thought to be the initiating factor of ALS and is strongly associated with mitochondrial dysfunction. […] Glutamate excitotoxicity: Glutamate receptor hyperstimulation may occur through several mechanisms, which include increased synaptic glutamate release, altered AMPARs, and decreased clearance of glutamate by astrocytes. […] Defective axonal transport is probably related to the ALS development. […] The UPR crosstalk with mitochondria has been shown to control programmed cell death.

• #57

  https://omim.org/entry/105400

  ALS is a genetically heterogeneous disorder, with several causative genes and mapped loci. […] Rothstein et al. (1992) found in in vitro studies that synaptosomes in neural tissue obtained from 13 ALS patients showed a marked decrease in the maximal velocity of transport for high-affinity glutamate uptake in spinal cord, motor cortex, and somatosensory cortex compared to controls. […] Liu et al. (1998) demonstrated increased free radical production in the spinal cord but not the brain of transgenic mice expressing mutant human SOD1 (G93A; 147450.0008), which preceded the degeneration of motor neurons. […] Li et al. (2000) demonstrated an 81.5% elevation of caspase-1 (CASP1; 147678) activity in the spinal cord of humans with ALS when compared with normal controls, and, using an animal model, suggested that caspases play an instrumental role in the neurodegenerative processing of ALS.

• #58 Pathophysiology of Amyotrophic Lateral Sclerosis | IntechOpen

  https://www.intechopen.com/chapters/45326

  Also, SOD1 mutations seem to disrupt RNA processing in the cells. […] A dominant hypothesis of ALS pathogenesis is glutamate excitotoxicity. […] In addition, defects in glutamate transport leading to elevated glutamate levels have been reported in mSOD1 mice and significant number of patients with sALS (Dunlop et al., Lin et al., Rothstein et al.,). […] The mechanism of glutamate neurotoxicity remains elusive. […] Excessive glutamate levels lead to activation of glutamate ionotropic AMPA receptors in neurons and glial cells. […] Mitochondrial malfunction is an important hypothesis in ALS pathogenesis (Bruijn et al., 2004; Manfredi et al., 2005). […] Indeed, mitochondria morphological and ultrastructural changes as well as bioenergetic malfunction have been reported in ALS. […] Abnormalities in mitochondrial calcium homeostasis were reported in ALS patients and in mutant SOD1 animals (Kruman et al., 1999; Carri et al., 1997; Reiner et al, 1995; Jaiswal et al., 2009).

• #59 The pathophysiology of amyotrophic lateral sclerosis (ALS) and the role of C9orf72

  https://www.linkedin.com/pulse/pathophysiology-amyotrophic-lateral-sclerosis-als-role-hoffman

  Morphological and ultrastructural deformities of mitochondria have been found in autopsies of patients with ALS. […] The correlation between ALS and pesticide exposure has been investigated in several studies. […] The C9orf72 gene is so special, because it lies in an intronic region and is transcribed, although normally only exons are transcribed, not introns. […] ALS has been related to the loss-of-function of the C9orf72 gene, gain-of-function of the C9orf72 gene via RNA repeats, gain-of-function via DPR protein, and finally the formation of G-quadruplexes. […] The manner of action in ALS is by way of sequestration of essential RNA-binding proteins into aggregates of repeat containing RNA foci, in the nucleus of the affected cell. […] The final genetical mechanism in ALS involves G-quadruplexes. The C9orf72 hexanucleotide repeat expansions DNA and RNA set up the formation of G-quadruplexes.

• #60 Pathophysiology of Amyotrophic Lateral Sclerosis | IntechOpen

  https://www.intechopen.com/chapters/45326

  Also, SOD1 mutations seem to disrupt RNA processing in the cells. […] A dominant hypothesis of ALS pathogenesis is glutamate excitotoxicity. […] In addition, defects in glutamate transport leading to elevated glutamate levels have been reported in mSOD1 mice and significant number of patients with sALS (Dunlop et al., Lin et al., Rothstein et al.,). […] The mechanism of glutamate neurotoxicity remains elusive. […] Excessive glutamate levels lead to activation of glutamate ionotropic AMPA receptors in neurons and glial cells. […] Mitochondrial malfunction is an important hypothesis in ALS pathogenesis (Bruijn et al., 2004; Manfredi et al., 2005). […] Indeed, mitochondria morphological and ultrastructural changes as well as bioenergetic malfunction have been reported in ALS. […] Abnormalities in mitochondrial calcium homeostasis were reported in ALS patients and in mutant SOD1 animals (Kruman et al., 1999; Carri et al., 1997; Reiner et al, 1995; Jaiswal et al., 2009).

• #61 Mechanism that causes ALS nerve destruction unveiled for first time

  https://www.drugtargetreview.com/news/100292/mechanism-that-causes-als-nerve-destruction-unveiled-for-first-time/

  The dysfunction of mitochondria in nerve terminals leads to neuromuscular junction disruption and the death of motor neurons. […] In our current study, we focused on a pathological change in TDP-43 protein that takes place in these axons and at neuromuscular junctions, Perlson continued. […] We showed that in ALS this protein exits the nucleus and accumulates throughout the entire cell and particularly in the neuromuscular junction. […] The team discovered that the accumulations formed by the TDP-43 protein in neuromuscular junctions trap RNA molecules and prevent the synthesis of proteins to mitochondrial function. […] The condensation of TDP-43 protein resulted in a severe energy depletion, prevented mitochondrial repair, and consequently led to the disruption of these junctions, the degeneration of the entire extension cable and to the death of motor neurons in the spinal cord.

• #62 Amyotrophic Lateral Sclerosis Signaling | GeneGlobe

  https://geneglobe.qiagen.com/us/knowledge/pathways/amyotrophic-lateral-sclerosis-signaling

  Amyotrophic lateral sclerosis (ALS, also called Maladie the Charcot or Lou Gehrig’s disease) is a progressive, usually fatal paralytic disorder caused by the degeneration of motor neurons. The cause of ALS is currently unknown, but appears to involve different mechanisms:1. Oxidative damage. Approximately 20% of all familial cases is linked to mutations in the gene for the cytosolic free radical-scavenging enzyme superoxide dismutase-1 (SOD1). Mutant SOD1 catalyses aberrant biochemical reactions, resulting in the production of potentially damaging reactive oxygen species, such as superoxide anion, hydroxyl radical, hydrogen peroxide and peroxynitrite. The neuronal oxidative damage seen in ALS could be generated by hydroxyl radical (Peroxidase hypothesis) and/or peroxynitrite (Peroxynitrie hypothesis).2. Glutamate-induced excitotoxicity. Neuronal membrane depolarization after activation of glutamate receptors activates voltage-dependent Ca2+ channels, which allows Ca2+ influx into the cell. Glutamate activity is regulated by receptor inactivation and glutamate reuptake by the transporter protein SLC1A2. It has been shown that this transporter level is reduced in motor cortex and spinal cord of ALS patients. Moreover, oxidative damage by ROS has been suggested as another possible mechanism by which the glutamate transporter SLC1A2 could be inactivated. Thus, this loss of glutamate transporter could lead to an excessive activation of glutamate receptors and a prolonged Ca2+ entry, which could cause excitotoxic degeneration of motor neurons.3. Neurofilament (NF) inclusion. A pathological hallmark of ALS is the presence of abnormal neurofilament inclusions in the perikaryon and axon of motor neurons. Extensive reduction in NF-L level has been demonstrated in degenerating motor neurons of ALS patients. This protein is required for proper neurofilament assembly and transport, therefore a lack of NF-L can provoke accumulation of NF-M and NF-H, which can lead to perikaryal neurofilament inclusions. Peripherin is another type of intermediate filament protein that has been identified in motor neuron inclusions in ALS patients. Peripherin heterodimerizes with each of the NF subunits to establish an intermediate filament network. However, because of the reduced level of NF-L, the interaction between peripherin and NF-M and NF-H results in disorganized network, triggering the formation of axonal peripherin inclusions.4. Impaired mitochondrial function. Mitochondrial degeneration, manifested by mitochondrial vacuolization, has been reported in ALS motor neurons. Mutant SOD1, upregulated proteins (Bax), downregulated proteins (Bcl-2, Bcl-xl) present in motor neurons of ALS patients initiate cytochrome c release from the mitochondria into the cytoplasm, which activates caspase-3, leading to motor neuron apoptosis. […] ALS pathogenesis involves multiple cascades of events including oxidative damage, excitotoxicity, aberrant protein aggregation, mitochondrial defects, and caspase activation, leading to motor neuron death in ALS patients.

• #63 Transmission of ALS pathogenesis by the cerebrospinal fluid | Acta Neuropathologica Communications | Full Text

  https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-020-00943-4

  The ALS-CSF exposure caused downregulation of several cytoskeletal proteins associated with microtubules and actin filaments, proteins involved in trafficking of vesicles and exosomal release, HSPs, proteins involved in axonal growth and glutamate secretion. […] Our results demonstrate that ALS-CSF infusion caused mitochondrial dysfunction in agreement with a previous study, adding mitochondrial aggregation and altered homeostasis to the repertoire.

• #64 Mechanism that causes ALS nerve destruction unveiled for first time

  https://www.drugtargetreview.com/news/100292/mechanism-that-causes-als-nerve-destruction-unveiled-for-first-time/

  The dysfunction of mitochondria in nerve terminals leads to neuromuscular junction disruption and the death of motor neurons. […] In our current study, we focused on a pathological change in TDP-43 protein that takes place in these axons and at neuromuscular junctions, Perlson continued. […] We showed that in ALS this protein exits the nucleus and accumulates throughout the entire cell and particularly in the neuromuscular junction. […] The team discovered that the accumulations formed by the TDP-43 protein in neuromuscular junctions trap RNA molecules and prevent the synthesis of proteins to mitochondrial function. […] The condensation of TDP-43 protein resulted in a severe energy depletion, prevented mitochondrial repair, and consequently led to the disruption of these junctions, the degeneration of the entire extension cable and to the death of motor neurons in the spinal cord.

• #65 Pathophysiology of Amyotrophic Lateral Sclerosis | IntechOpen

  https://www.intechopen.com/chapters/45326

  Despite of all these discoveries the etiology of ALS remains elusive. A number of potential pathogenic mechanisms have been associated with ALS including excitotoxicity, mitochondrial dysfunction, apoptosis, glial activation, RNA-processing, growth factor abnormalities, etc. These potential pathogenic processes are reviewed in this chapter. […] The hallmark finding of lower motor neuron (LMN) pathology in ALS is the presence of intracellular inclusion bodies in neuronal soma and proximal dendrites as well as glia (Barbeito et al., 2004). […] Mutations in the gene of copper/zinc superoxide dismutase type 1 (SOD1) are the most common cause of fALS (Rothstein, 2009; Boillee and Cleveland, 2008; Robberecht and Phillips, 2013). […] Recent reports indicate that SOD1 mutations may also be the cause of between 0.7 – 4% cases of sporadic ALS (sALS) (Robberecht and Phillips, 2013).

• #66

  https://journals.lww.com/nrronline/fulltext/2024/05000/pathological_mechanisms_of_amyotrophic_lateral.32.aspx

  Neuroinflammation has been suggested to play a key role within ALS disease onset and progression. […] Activated microglia can activate astrocyte neurotoxicity by secreting inflammatory factors. […] Impaired proteostasis: Aggregated pathological proteins can accumulate in the cytoplasm in large quantities. […] Oxidative stress has been thought to be the initiating factor of ALS and is strongly associated with mitochondrial dysfunction. […] Glutamate excitotoxicity: Glutamate receptor hyperstimulation may occur through several mechanisms, which include increased synaptic glutamate release, altered AMPARs, and decreased clearance of glutamate by astrocytes. […] Defective axonal transport is probably related to the ALS development. […] The UPR crosstalk with mitochondria has been shown to control programmed cell death.

• #67 Amyotrophic Lateral Sclerosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1170097-overview

  In familial ALS due to an SOD1 mutation, the altered gene product is (1) the agent of spread of the disease in the motor network and (2) its accumulation and aggregation in motor neurons leads to their demise. […] In contrast, TDP-43 is a nuclear-to-cytoplasmic mRNA transporter protein that misfolds and precipitates in the motor neuronal cytoplasm of patients with sporadic ALS /FTLD and most cases of familial ALS/ FTLD, including but not limited to those inheriting a mutated TDP-43 gene. […] ALS should not be considered a single disease entity, but rather a clinical diagnosis for different pathophysiologic cascades that share the common consequence of causing preferential progressive loss of motor neurons and the orderly dismantling of the motor neuron system. […] Previously, research into the mechanisms resulting in sporadic and familial types of ALS had examined several possibilities. For example, excitotoxicity was suggested to occur secondary to overactivation of glutamate receptors.

• #68 Amyotrophic Lateral Sclerosis: Molecular Mechanisms, Biomarkers, and Therapeutic Strategies

  https://www.mdpi.com/2076-3921/10/7/1012

  Autophagy is therefore considered to be an important neuroprotective pathway. However, patients with ALS appear to have specific autophagy dysfunction in glial cells. […] Studies have shown that disordered iron homeostasis in the central nervous system contributes to disease progression in the mouse ALS model. […] Overall, redox imbalance is a well-recognized phenomenon in the pathogenesis of ALS. […] The pathogenesis of ALS is intricately related to immune cell population, complements, cytokines, and a series of immune inflammatory markers. […] The disorder of the immune system is an important cause of ALS; however, the specific molecular mechanisms need to be further explored.

• #69

  https://journals.lww.com/nrronline/fulltext/2024/05000/pathological_mechanisms_of_amyotrophic_lateral.32.aspx

  Studies indicate that a central role in ALS pathogenesis is played by ER stress and aberrant UPR and that activating ER stress-induced autophagy may increase cytotoxicity. […] The majority of evidence indicates that neurodegeneration induced by C9ORF72 HRE is largely dependent upon the mechanism of toxic acquisition. […] The specific pathogenic mechanisms of ALS remain unresolved after many years of research, the pathophysiological mechanisms of the disease may be due to a combination of mechanisms mediated via complicated interactions among molecular and genetic pathways rather than a single factor.

• #70 Amyotrophic Lateral Sclerosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1170097-overview

  Despite such research, no direct mechanism for ALS has been identified. Most investigators and clinicians agree that various factors, possibly a combination of some or all of the above processes, may lead to development of the disease. […] If ALS is considered under the umbrella of neuronal system degenerative diseases, then the specificity for the motor system attacked by the disorder can be attributed to a pathologic process that arises within and spreads through the motor neuron system. […] Prionlike propagation of misfolding of proteins in particular, SOD1 and the 43 kDa transactive response DNA binding protein (TDP-43) has been proposed as a mechanism for the regional spread of ALS symptoms. […] Motor axons die by Wallerian degeneration in ALS, and large motor neurons are affected to a greater extent than smaller ones.

• #71 Advances and challenges in understanding the multifaceted pathogenesis of amyotrophic lateral sclerosis

  https://smw.ch/index.php/smw/article/download/1990/2861?inline=1

  Several cytotoxic mechanisms have been described for C9ORF72 hexanucleotide repeat expansions and their relative contribution to ALS pathogenesis is currently under investigation. […] The physiological function of a protein is often linked to a unique structure and stable three-dimensional conformation, as a result of a normal folding pathway. Some proteins can gain toxic properties upon a disturbance of their structure that can stably exist and be transferred to homologous proteins if their structure allows this pathological conformation. This mechanism underlies the pathogenesis of prion diseases, and is suggested to contribute to the progression of many neurodegenerative diseases, such as Alzheimers and Parkinsons diseases. […] The aggregation properties of TDP-43 and FUS are associated with their physiological role in the formation of stress granules. […] All above mechanisms may contribute to C9ORF72 disease and the spreading of TDP-43 pathology in patients with hexanucleotide repeat expansions. […] In conclusion, ALS is complex and heterogeneous disease that is caused by many, seemingly diverse, upstream events.

• #72

  https://journals.lww.com/nrronline/fulltext/2024/05000/pathological_mechanisms_of_amyotrophic_lateral.32.aspx

  At present, ALS pathogenesis is still unclear, as it involves a very large number of cellular processes, so it is still difficult to determine which of these are pathogenic factors. […] Although the specific pathogenic mechanisms of ALS remain unresolved after many years of research, the pathophysiological mechanisms of the disease may be due to a combination of mechanisms mediated via complicated interactions among molecular and genetic pathways rather than a single factor. […] A variety of disease mechanisms have been suggested, which include glutamate excitotoxicity, free radical-mediated oxidative stress, structural and functional abnormalities in mitochondria, proteostasis, abnormal RNA metabolism, nucleocytoplasmic transport detects, impaired DNA damage and DNA repair, neuroinflammation, oligodendrocyte dysfunction, and axonal transport defects.

• #73 Pathogenetic mechanisms of amyotrophic lateral sclerosis – Aktualności Neurologiczne – Current Neurology

  https://www.neurologia.com.pl/index.php/issues/2012-vol-12-no-4/pathogenetic-mechanisms-of-amyotrophic-lateral-sclerosis

  Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, resulting in a damage of motor neurons. Pathogenesis of ALS is most probably multifactorial, complex and not entirely elucidated. It may involve such mechanisms as oxidative stress, toxicity of glutamic acid, dysfunction of the mitochondria, stress of endoplasmic reticulum, aggregation of proteins, dysfunction of the cytoskeleton, disturbed axonal transport, role of glial cells, neuroinflammatory process, lactic acid dyscrasia, and genetic factors. An important cause of oxidative stress in ALS are mutations of superoxide dismutase 1 (SOD1) gene leading to altered activity of the enzyme and its enhanced toxicity. Abnormal SOD1 participates in inflammatory response of activated astrocytes and microglia in the spinal cord of ALS patients. Mechanisms of oxidative stress and glutamate toxicity are coupled together. Death of motor neurons occurs as a result if activation of caspases and apoptosis, while mitochondrial dysfunction merely participates in the process. Pathomorphological alterations within the endoplasmic reticulum are present already at an early phase of the disease and indicate that stress within this structure plays an important role in the ALS-related process of neurodegeneration. Another interesting feature of ALS are alterations of cytoskeleton, concerning mainly neurofilaments. According to the hypothesis of lactic acid dyscrasia, dysregulation of myoneuronal lactic acid channel results in cellular stress, toxicity and progressive degeneration. An important role in the pathogenesis of ALS may be also played by genetic mutations of proteins other than SOD1.

• #74 Amyotrophic Lateral Sclerosis Signaling | GeneGlobe

  https://geneglobe.qiagen.com/us/knowledge/pathways/amyotrophic-lateral-sclerosis-signaling

  Amyotrophic lateral sclerosis (ALS, also called Maladie the Charcot or Lou Gehrig’s disease) is a progressive, usually fatal paralytic disorder caused by the degeneration of motor neurons. The cause of ALS is currently unknown, but appears to involve different mechanisms:1. Oxidative damage. Approximately 20% of all familial cases is linked to mutations in the gene for the cytosolic free radical-scavenging enzyme superoxide dismutase-1 (SOD1). Mutant SOD1 catalyses aberrant biochemical reactions, resulting in the production of potentially damaging reactive oxygen species, such as superoxide anion, hydroxyl radical, hydrogen peroxide and peroxynitrite. The neuronal oxidative damage seen in ALS could be generated by hydroxyl radical (Peroxidase hypothesis) and/or peroxynitrite (Peroxynitrie hypothesis).2. Glutamate-induced excitotoxicity. Neuronal membrane depolarization after activation of glutamate receptors activates voltage-dependent Ca2+ channels, which allows Ca2+ influx into the cell. Glutamate activity is regulated by receptor inactivation and glutamate reuptake by the transporter protein SLC1A2. It has been shown that this transporter level is reduced in motor cortex and spinal cord of ALS patients. Moreover, oxidative damage by ROS has been suggested as another possible mechanism by which the glutamate transporter SLC1A2 could be inactivated. Thus, this loss of glutamate transporter could lead to an excessive activation of glutamate receptors and a prolonged Ca2+ entry, which could cause excitotoxic degeneration of motor neurons.3. Neurofilament (NF) inclusion. A pathological hallmark of ALS is the presence of abnormal neurofilament inclusions in the perikaryon and axon of motor neurons. Extensive reduction in NF-L level has been demonstrated in degenerating motor neurons of ALS patients. This protein is required for proper neurofilament assembly and transport, therefore a lack of NF-L can provoke accumulation of NF-M and NF-H, which can lead to perikaryal neurofilament inclusions. Peripherin is another type of intermediate filament protein that has been identified in motor neuron inclusions in ALS patients. Peripherin heterodimerizes with each of the NF subunits to establish an intermediate filament network. However, because of the reduced level of NF-L, the interaction between peripherin and NF-M and NF-H results in disorganized network, triggering the formation of axonal peripherin inclusions.4. Impaired mitochondrial function. Mitochondrial degeneration, manifested by mitochondrial vacuolization, has been reported in ALS motor neurons. Mutant SOD1, upregulated proteins (Bax), downregulated proteins (Bcl-2, Bcl-xl) present in motor neurons of ALS patients initiate cytochrome c release from the mitochondria into the cytoplasm, which activates caspase-3, leading to motor neuron apoptosis. […] ALS pathogenesis involves multiple cascades of events including oxidative damage, excitotoxicity, aberrant protein aggregation, mitochondrial defects, and caspase activation, leading to motor neuron death in ALS patients.

• #75 Amyotrophic Lateral Sclerosis Signaling | GeneGlobe

  https://geneglobe.qiagen.com/us/knowledge/pathways/amyotrophic-lateral-sclerosis-signaling

  Amyotrophic lateral sclerosis (ALS, also called Maladie the Charcot or Lou Gehrig’s disease) is a progressive, usually fatal paralytic disorder caused by the degeneration of motor neurons. The cause of ALS is currently unknown, but appears to involve different mechanisms:1. Oxidative damage. Approximately 20% of all familial cases is linked to mutations in the gene for the cytosolic free radical-scavenging enzyme superoxide dismutase-1 (SOD1). Mutant SOD1 catalyses aberrant biochemical reactions, resulting in the production of potentially damaging reactive oxygen species, such as superoxide anion, hydroxyl radical, hydrogen peroxide and peroxynitrite. The neuronal oxidative damage seen in ALS could be generated by hydroxyl radical (Peroxidase hypothesis) and/or peroxynitrite (Peroxynitrie hypothesis).2. Glutamate-induced excitotoxicity. Neuronal membrane depolarization after activation of glutamate receptors activates voltage-dependent Ca2+ channels, which allows Ca2+ influx into the cell. Glutamate activity is regulated by receptor inactivation and glutamate reuptake by the transporter protein SLC1A2. It has been shown that this transporter level is reduced in motor cortex and spinal cord of ALS patients. Moreover, oxidative damage by ROS has been suggested as another possible mechanism by which the glutamate transporter SLC1A2 could be inactivated. Thus, this loss of glutamate transporter could lead to an excessive activation of glutamate receptors and a prolonged Ca2+ entry, which could cause excitotoxic degeneration of motor neurons.3. Neurofilament (NF) inclusion. A pathological hallmark of ALS is the presence of abnormal neurofilament inclusions in the perikaryon and axon of motor neurons. Extensive reduction in NF-L level has been demonstrated in degenerating motor neurons of ALS patients. This protein is required for proper neurofilament assembly and transport, therefore a lack of NF-L can provoke accumulation of NF-M and NF-H, which can lead to perikaryal neurofilament inclusions. Peripherin is another type of intermediate filament protein that has been identified in motor neuron inclusions in ALS patients. Peripherin heterodimerizes with each of the NF subunits to establish an intermediate filament network. However, because of the reduced level of NF-L, the interaction between peripherin and NF-M and NF-H results in disorganized network, triggering the formation of axonal peripherin inclusions.4. Impaired mitochondrial function. Mitochondrial degeneration, manifested by mitochondrial vacuolization, has been reported in ALS motor neurons. Mutant SOD1, upregulated proteins (Bax), downregulated proteins (Bcl-2, Bcl-xl) present in motor neurons of ALS patients initiate cytochrome c release from the mitochondria into the cytoplasm, which activates caspase-3, leading to motor neuron apoptosis. […] ALS pathogenesis involves multiple cascades of events including oxidative damage, excitotoxicity, aberrant protein aggregation, mitochondrial defects, and caspase activation, leading to motor neuron death in ALS patients.

• #76

  https://journals.lww.com/nrronline/fulltext/2024/05000/pathological_mechanisms_of_amyotrophic_lateral.32.aspx

  Neuroinflammation has been suggested to play a key role within ALS disease onset and progression. […] Activated microglia can activate astrocyte neurotoxicity by secreting inflammatory factors. […] Impaired proteostasis: Aggregated pathological proteins can accumulate in the cytoplasm in large quantities. […] Oxidative stress has been thought to be the initiating factor of ALS and is strongly associated with mitochondrial dysfunction. […] Glutamate excitotoxicity: Glutamate receptor hyperstimulation may occur through several mechanisms, which include increased synaptic glutamate release, altered AMPARs, and decreased clearance of glutamate by astrocytes. […] Defective axonal transport is probably related to the ALS development. […] The UPR crosstalk with mitochondria has been shown to control programmed cell death.

• #77 Amyotrophic Lateral Sclerosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1170097-overview

  Despite such research, no direct mechanism for ALS has been identified. Most investigators and clinicians agree that various factors, possibly a combination of some or all of the above processes, may lead to development of the disease. […] If ALS is considered under the umbrella of neuronal system degenerative diseases, then the specificity for the motor system attacked by the disorder can be attributed to a pathologic process that arises within and spreads through the motor neuron system. […] Prionlike propagation of misfolding of proteins in particular, SOD1 and the 43 kDa transactive response DNA binding protein (TDP-43) has been proposed as a mechanism for the regional spread of ALS symptoms. […] Motor axons die by Wallerian degeneration in ALS, and large motor neurons are affected to a greater extent than smaller ones.

• #78 Pathophysiology of Amyotrophic Lateral Sclerosis — Firstclass

  https://www.firstclassmed.com/articles/2023/pathophysiology-of-als

  Understand that the genetic mutations set the stage for the other pathogenetic processes to take place. Without them, the disease would not occur. Of the subsequent processes, research has shown that excitotoxicity is the most prevalent pathogenetic mechanism which leads to motor neurone damage in ALS. […] Excitotoxicity is the dominant hypothesis of ALS pathogenesis. Glutamate is the major excitatory neurotransmitter in mammalian CNS but in high concentrations, glutamate is toxic to neurones. […] The motor neurones die through Wallerian degeneration. The death of one neurone leads to axonal degeneration and death. […] When the denervation exceeds the renervation process, clinical features manifest themselves. Progressive denervation leads to atrophy of the whole muscle causing amyotrophy. […] As the damage extends to the cortical motor neurones, there is thinning of the corticospinal tracts. These tracts travel the lateral and anterior part of the spinal cord. Progressive loss of fibers leads to gliosis which makes the tracts firm which appears as lateral sclerosis on autopsy.

• #79 Amyotrophic Lateral Sclerosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1170097-overview

  Despite such research, no direct mechanism for ALS has been identified. Most investigators and clinicians agree that various factors, possibly a combination of some or all of the above processes, may lead to development of the disease. […] If ALS is considered under the umbrella of neuronal system degenerative diseases, then the specificity for the motor system attacked by the disorder can be attributed to a pathologic process that arises within and spreads through the motor neuron system. […] Prionlike propagation of misfolding of proteins in particular, SOD1 and the 43 kDa transactive response DNA binding protein (TDP-43) has been proposed as a mechanism for the regional spread of ALS symptoms. […] Motor axons die by Wallerian degeneration in ALS, and large motor neurons are affected to a greater extent than smaller ones.

• #80 Why do motor neurons degenerate? Actualisation in the pathogenesis of amyotrophic lateral sclerosis | Neurología (English Edition)

  https://www.elsevier.es/en-revista-neurologia-english-edition-495-articulo-why-do-motor-neurons-degenerate-S2173580817301633

  Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons. Although a small proportion of ALS cases are familial in origin and linked to mutations in specific genes, most cases are sporadic and have a multifactorial aetiology. Some recent studies have increased our knowledge of ALS pathogenesis and raised the question of whether this disorder is a proteinopathy, a ribonucleopathy, an axonopathy, or a disease related to the neuronal microenvironment. […] ALS pathogenesis has not been fully elucidated. Recent studies suggest that although initial triggers may differ among patients, the final motor neurons degeneration mechanisms are similar in most patients once the disease is fully established. […] ALS specifically affects cells, leading to tissue alterations; the most frequently affected cells are motor neurons. Although the precise factors determining preferential involvement of motor neurons are yet to be fully understood, certain factors have been associated with the particular vulnerability of these cells: (1) the large size of the cells and their robust cytoskeleton, which has high metabolic demands to maintain cell functions; (2) high reliance on optimal mitochondrial function; (3) high vulnerability to excitotoxicity and dysregulation of intracellular calcium homeostasis; and (4) reduced capacity for heat shock response and chaperone activity, and possibly reduced function of the ubiquitin proteasome system.

• #81 Pathophysiology of Amyotrophic Lateral Sclerosis | IntechOpen

  https://www.intechopen.com/chapters/45326

  Evidence is accumulating indicating that motor neuron degeneration in ALS is not only restricted to neuronal autonomous cell death but it is rather a more complex process involving inflammatory neurotoxicity from non-neuronal glial cells such as astrocytes and microglia (Phani et al., 2012). […] Apoptosis is a programmed cell death cascade involved in several physiological processes during development and aging. […] There is compelling evidence in ALS, at least in mutant SOD1-ALS, that toxicity is mediated by apoptosis. […] The research in the ALS field encounters many limitations, what is clearly reflected in the little progress accomplished in the therapy of this neurodegenerative disorder.

• #82

  https://journals.lww.com/nrronline/fulltext/2024/05000/pathological_mechanisms_of_amyotrophic_lateral.32.aspx

  Neuroinflammation has been suggested to play a key role within ALS disease onset and progression. […] Activated microglia can activate astrocyte neurotoxicity by secreting inflammatory factors. […] Impaired proteostasis: Aggregated pathological proteins can accumulate in the cytoplasm in large quantities. […] Oxidative stress has been thought to be the initiating factor of ALS and is strongly associated with mitochondrial dysfunction. […] Glutamate excitotoxicity: Glutamate receptor hyperstimulation may occur through several mechanisms, which include increased synaptic glutamate release, altered AMPARs, and decreased clearance of glutamate by astrocytes. […] Defective axonal transport is probably related to the ALS development. […] The UPR crosstalk with mitochondria has been shown to control programmed cell death.

• #83

  https://journals.lww.com/nrronline/fulltext/2024/05000/pathological_mechanisms_of_amyotrophic_lateral.32.aspx

  Neuroinflammation has been suggested to play a key role within ALS disease onset and progression. […] Activated microglia can activate astrocyte neurotoxicity by secreting inflammatory factors. […] Impaired proteostasis: Aggregated pathological proteins can accumulate in the cytoplasm in large quantities. […] Oxidative stress has been thought to be the initiating factor of ALS and is strongly associated with mitochondrial dysfunction. […] Glutamate excitotoxicity: Glutamate receptor hyperstimulation may occur through several mechanisms, which include increased synaptic glutamate release, altered AMPARs, and decreased clearance of glutamate by astrocytes. […] Defective axonal transport is probably related to the ALS development. […] The UPR crosstalk with mitochondria has been shown to control programmed cell death.

• #84 Why do motor neurons degenerate? Actualisation in the pathogenesis of amyotrophic lateral sclerosis | Neurología (English Edition)

  https://www.elsevier.es/en-revista-neurologia-english-edition-495-articulo-why-do-motor-neurons-degenerate-S2173580817301633

  Some studies including patients with this expansion have shown that their levels of C9ORF72 mRNA were up to 50% lower, which suggests that the mutant allele is probably unable to produce mature RNA; this would be linked to the hypothesis of a loss-of-function process. […] In addition to the damage it causes directly, oxidative stress promotes other pathogenic mechanisms which contribute to neuronal alterations, including excitotoxicity, protein aggregation, ER stress response, and mitochondrial dysfunction, and it also affects the interaction between motor neurons and the neuronal microenvironment. […] Although motor neuron degeneration and loss is the main finding in patients with ALS, the condition has also been associated with activation of a neuroinflammatory response. […] This inflammatory response contributes to the progressive degeneration and phenotypic alteration of motor neurons, starting with the first manifestations of the disease.

• #85

  https://journals.lww.com/nrronline/fulltext/2024/05000/pathological_mechanisms_of_amyotrophic_lateral.32.aspx

  At present, ALS pathogenesis is still unclear, as it involves a very large number of cellular processes, so it is still difficult to determine which of these are pathogenic factors. […] Although the specific pathogenic mechanisms of ALS remain unresolved after many years of research, the pathophysiological mechanisms of the disease may be due to a combination of mechanisms mediated via complicated interactions among molecular and genetic pathways rather than a single factor. […] A variety of disease mechanisms have been suggested, which include glutamate excitotoxicity, free radical-mediated oxidative stress, structural and functional abnormalities in mitochondria, proteostasis, abnormal RNA metabolism, nucleocytoplasmic transport detects, impaired DNA damage and DNA repair, neuroinflammation, oligodendrocyte dysfunction, and axonal transport defects.

• #86 Why do motor neurons degenerate? Actualisation in the pathogenesis of amyotrophic lateral sclerosis | Neurología (English Edition)

  https://www.elsevier.es/en-revista-neurologia-english-edition-495-articulo-why-do-motor-neurons-degenerate-S2173580817301633

  Some studies including patients with this expansion have shown that their levels of C9ORF72 mRNA were up to 50% lower, which suggests that the mutant allele is probably unable to produce mature RNA; this would be linked to the hypothesis of a loss-of-function process. […] In addition to the damage it causes directly, oxidative stress promotes other pathogenic mechanisms which contribute to neuronal alterations, including excitotoxicity, protein aggregation, ER stress response, and mitochondrial dysfunction, and it also affects the interaction between motor neurons and the neuronal microenvironment. […] Although motor neuron degeneration and loss is the main finding in patients with ALS, the condition has also been associated with activation of a neuroinflammatory response. […] This inflammatory response contributes to the progressive degeneration and phenotypic alteration of motor neurons, starting with the first manifestations of the disease.

• #87

  https://journals.lww.com/nrronline/fulltext/2024/05000/pathological_mechanisms_of_amyotrophic_lateral.32.aspx

  The dying forward hypothesis suggests that ALS has cortical origins that involves the corticospinal MNs, which are connected to the MNs in the spinal cord by monosynaptic connections and mediated by glutamate excitotoxicity, leading to MN degeneration along the axon. […] The dying back hypothesis states that lower MN dysfunction occurs early in ALS disease, possibly due to its origin in the muscle or neuromuscular junction, with retrograde transport of harmful factors into the axonal cell bodies from the periphery, resulting in toxicity, a phenomenon that may be associated with axoplasmic transport associated with dysfunction. […] The independent degeneration hypothesis that states that degenerative lesions of the corticospinal and lower MNs occur separately and randomly and are thought to propagate along their respective neuroanatomical structures.

• #88 Pathogenesis and Presentation of ALS: Examining Reasons for Delayed Diagnosis and Identifying Opportunities for Improvement

  https://www.ajmc.com/view/pathogenesis-and-presentation-of-als-examining-reasons-for-delayed-diagnosis-and-identifying-opportunities-for-improvement

  Amyotrophic lateral sclerosis (ALS), or Lou Gehrig disease, is a progressive, always-fatal neuromuscular disease characterized by motor neuron degeneration in the brain and spinal cord. […] Experts consider oxidative stress, reactive oxygen species (ROS), and glutamate excitotoxicity to be the main contributing factors to ALS progression. […] Unrestricted glutamate secretion at synaptic junctions overstimulates motor neurons receiving signals. […] ALS pathogenesis exploits the relationship between UMN and LMN. […] Simultaneous involvement of UMN and LMN distinguishes typical ALS from atypical ALS phenotypes and other motor neuron diseases. […] Three major hypotheses discuss ALS onset: Dying forward hypothesis: ALS is primarily a UMN disorder, which causes anterograde degeneration through glutamate excitotoxicity.

• #89

  https://journals.lww.com/nrronline/fulltext/2024/05000/pathological_mechanisms_of_amyotrophic_lateral.32.aspx

  The dying forward hypothesis suggests that ALS has cortical origins that involves the corticospinal MNs, which are connected to the MNs in the spinal cord by monosynaptic connections and mediated by glutamate excitotoxicity, leading to MN degeneration along the axon. […] The dying back hypothesis states that lower MN dysfunction occurs early in ALS disease, possibly due to its origin in the muscle or neuromuscular junction, with retrograde transport of harmful factors into the axonal cell bodies from the periphery, resulting in toxicity, a phenomenon that may be associated with axoplasmic transport associated with dysfunction. […] The independent degeneration hypothesis that states that degenerative lesions of the corticospinal and lower MNs occur separately and randomly and are thought to propagate along their respective neuroanatomical structures.

• #90 Pathogenesis and Presentation of ALS: Examining Reasons for Delayed Diagnosis and Identifying Opportunities for Improvement

  https://www.ajmc.com/view/pathogenesis-and-presentation-of-als-examining-reasons-for-delayed-diagnosis-and-identifying-opportunities-for-improvement

  Amyotrophic lateral sclerosis (ALS), or Lou Gehrig disease, is a progressive, always-fatal neuromuscular disease characterized by motor neuron degeneration in the brain and spinal cord. […] Experts consider oxidative stress, reactive oxygen species (ROS), and glutamate excitotoxicity to be the main contributing factors to ALS progression. […] Unrestricted glutamate secretion at synaptic junctions overstimulates motor neurons receiving signals. […] ALS pathogenesis exploits the relationship between UMN and LMN. […] Simultaneous involvement of UMN and LMN distinguishes typical ALS from atypical ALS phenotypes and other motor neuron diseases. […] Three major hypotheses discuss ALS onset: Dying forward hypothesis: ALS is primarily a UMN disorder, which causes anterograde degeneration through glutamate excitotoxicity.

• #91

  https://journals.lww.com/nrronline/fulltext/2024/05000/pathological_mechanisms_of_amyotrophic_lateral.32.aspx

  The dying forward hypothesis suggests that ALS has cortical origins that involves the corticospinal MNs, which are connected to the MNs in the spinal cord by monosynaptic connections and mediated by glutamate excitotoxicity, leading to MN degeneration along the axon. […] The dying back hypothesis states that lower MN dysfunction occurs early in ALS disease, possibly due to its origin in the muscle or neuromuscular junction, with retrograde transport of harmful factors into the axonal cell bodies from the periphery, resulting in toxicity, a phenomenon that may be associated with axoplasmic transport associated with dysfunction. […] The independent degeneration hypothesis that states that degenerative lesions of the corticospinal and lower MNs occur separately and randomly and are thought to propagate along their respective neuroanatomical structures.

• #92 Pathogenesis and Presentation of ALS: Examining Reasons for Delayed Diagnosis and Identifying Opportunities for Improvement

  https://www.ajmc.com/view/pathogenesis-and-presentation-of-als-examining-reasons-for-delayed-diagnosis-and-identifying-opportunities-for-improvement

  Dying back hypothesis: ALS begins within the muscles or at the neuromuscular junction and noxious factors transport back from the periphery to the axon cell body to exert harmful effects. […] Independent degeneration hypothesis: UMN and LMN degeneration occurs independently. […] Wherever the disease originates, maximal UMN and LMN degeneration occurs. […] With contiguous spread, degeneration occurs independently at UMN and LMN levels. […] ALS carries a significant burden and poor prognosis. […] Factors that negatively affect prognosis include neurofilament light chain levels (a marker of neurodegeneration), frontotemporal dementia, changes in ALS Functional Rating Scale-Revised (ALSFRS-R), respiratory subtype, executive dysfunction, and age at onset. […] Factors that positively affect prognosis include pure-LMN or pure-UMN subtypes (vs typical ALS), delay in diagnosis/disease duration, and baseline ALSFRS-R score.

• #93

  https://journals.lww.com/nrronline/fulltext/2024/05000/pathological_mechanisms_of_amyotrophic_lateral.32.aspx

  The dying forward hypothesis suggests that ALS has cortical origins that involves the corticospinal MNs, which are connected to the MNs in the spinal cord by monosynaptic connections and mediated by glutamate excitotoxicity, leading to MN degeneration along the axon. […] The dying back hypothesis states that lower MN dysfunction occurs early in ALS disease, possibly due to its origin in the muscle or neuromuscular junction, with retrograde transport of harmful factors into the axonal cell bodies from the periphery, resulting in toxicity, a phenomenon that may be associated with axoplasmic transport associated with dysfunction. […] The independent degeneration hypothesis that states that degenerative lesions of the corticospinal and lower MNs occur separately and randomly and are thought to propagate along their respective neuroanatomical structures.

• #94 Pathogenesis and Presentation of ALS: Examining Reasons for Delayed Diagnosis and Identifying Opportunities for Improvement

  https://www.ajmc.com/view/pathogenesis-and-presentation-of-als-examining-reasons-for-delayed-diagnosis-and-identifying-opportunities-for-improvement

  Dying back hypothesis: ALS begins within the muscles or at the neuromuscular junction and noxious factors transport back from the periphery to the axon cell body to exert harmful effects. […] Independent degeneration hypothesis: UMN and LMN degeneration occurs independently. […] Wherever the disease originates, maximal UMN and LMN degeneration occurs. […] With contiguous spread, degeneration occurs independently at UMN and LMN levels. […] ALS carries a significant burden and poor prognosis. […] Factors that negatively affect prognosis include neurofilament light chain levels (a marker of neurodegeneration), frontotemporal dementia, changes in ALS Functional Rating Scale-Revised (ALSFRS-R), respiratory subtype, executive dysfunction, and age at onset. […] Factors that positively affect prognosis include pure-LMN or pure-UMN subtypes (vs typical ALS), delay in diagnosis/disease duration, and baseline ALSFRS-R score.

• #95

  https://journals.lww.com/nrronline/fulltext/2024/05000/pathological_mechanisms_of_amyotrophic_lateral.32.aspx

  Studies indicate that a central role in ALS pathogenesis is played by ER stress and aberrant UPR and that activating ER stress-induced autophagy may increase cytotoxicity. […] The majority of evidence indicates that neurodegeneration induced by C9ORF72 HRE is largely dependent upon the mechanism of toxic acquisition. […] The specific pathogenic mechanisms of ALS remain unresolved after many years of research, the pathophysiological mechanisms of the disease may be due to a combination of mechanisms mediated via complicated interactions among molecular and genetic pathways rather than a single factor.

• #96 New insights into the pathogenesis of amyotrophic lateral sclerosis

  https://medicalxpress.com/news/2024-08-insights-pathogenesis-amyotrophic-lateral-sclerosis.html

  New insights into the pathogenesis of amyotrophic lateral sclerosis […] The metabolism of glucose in the brain is altered in people with a specific ALS-linked genetic mutation, called C9-NRE, and this change occurs many years before the onset of muscle weakening that characterizes the disease. […] Neuronal dysfunction, in turn, further undermines energy pathways in a vicious cycle of stress responses. This feedforward loop of problems that the researchers observed in cell culture and in animal models likely plays a role in the neurodegeneration seen in ALS patients. […] In carefully teasing out the molecular pathways involved, Dr. Trotti says he hopes to identify potential therapeutic targets whereby a drug might interrupt the chain reaction. The idea is to prevent the triggering event and hopefully stave off or slow down disease progression in patients with the genetic mutation. […] Dr. Trotti has hope for medications that are prescribed for diabetes, a condition that also involves altered glucose metabolism. Testing such drugs in preclinical models is the next step to see if they correct the metabolic imbalance.

• #97 Amyotrophic Lateral Sclerosis Signaling | GeneGlobe

  https://geneglobe.qiagen.com/us/knowledge/pathways/amyotrophic-lateral-sclerosis-signaling

  Amyotrophic lateral sclerosis (ALS, also called Maladie the Charcot or Lou Gehrig’s disease) is a progressive, usually fatal paralytic disorder caused by the degeneration of motor neurons. The cause of ALS is currently unknown, but appears to involve different mechanisms:1. Oxidative damage. Approximately 20% of all familial cases is linked to mutations in the gene for the cytosolic free radical-scavenging enzyme superoxide dismutase-1 (SOD1). Mutant SOD1 catalyses aberrant biochemical reactions, resulting in the production of potentially damaging reactive oxygen species, such as superoxide anion, hydroxyl radical, hydrogen peroxide and peroxynitrite. The neuronal oxidative damage seen in ALS could be generated by hydroxyl radical (Peroxidase hypothesis) and/or peroxynitrite (Peroxynitrie hypothesis).2. Glutamate-induced excitotoxicity. Neuronal membrane depolarization after activation of glutamate receptors activates voltage-dependent Ca2+ channels, which allows Ca2+ influx into the cell. Glutamate activity is regulated by receptor inactivation and glutamate reuptake by the transporter protein SLC1A2. It has been shown that this transporter level is reduced in motor cortex and spinal cord of ALS patients. Moreover, oxidative damage by ROS has been suggested as another possible mechanism by which the glutamate transporter SLC1A2 could be inactivated. Thus, this loss of glutamate transporter could lead to an excessive activation of glutamate receptors and a prolonged Ca2+ entry, which could cause excitotoxic degeneration of motor neurons.3. Neurofilament (NF) inclusion. A pathological hallmark of ALS is the presence of abnormal neurofilament inclusions in the perikaryon and axon of motor neurons. Extensive reduction in NF-L level has been demonstrated in degenerating motor neurons of ALS patients. This protein is required for proper neurofilament assembly and transport, therefore a lack of NF-L can provoke accumulation of NF-M and NF-H, which can lead to perikaryal neurofilament inclusions. Peripherin is another type of intermediate filament protein that has been identified in motor neuron inclusions in ALS patients. Peripherin heterodimerizes with each of the NF subunits to establish an intermediate filament network. However, because of the reduced level of NF-L, the interaction between peripherin and NF-M and NF-H results in disorganized network, triggering the formation of axonal peripherin inclusions.4. Impaired mitochondrial function. Mitochondrial degeneration, manifested by mitochondrial vacuolization, has been reported in ALS motor neurons. Mutant SOD1, upregulated proteins (Bax), downregulated proteins (Bcl-2, Bcl-xl) present in motor neurons of ALS patients initiate cytochrome c release from the mitochondria into the cytoplasm, which activates caspase-3, leading to motor neuron apoptosis. […] ALS pathogenesis involves multiple cascades of events including oxidative damage, excitotoxicity, aberrant protein aggregation, mitochondrial defects, and caspase activation, leading to motor neuron death in ALS patients.

• #98 Amyotrophic Lateral Sclerosis: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/1170097-overview

  Pathways that lead to cell death in ALS may be mediated by the following: oxidative damage, mitochondrial dysfunction, caspase-mediated cell death (apoptosis), defects in axonal transport, abnormal growth factor expression, glial cell pathology, glutamate excitotoxicity, aggregation of abnormal proteins. […] The findings below have placed derangements of RNA metabolism at the core of current thinking with regard to the pathophysiology of most types of ALS. […] Making the distinction between the pathogenesis and pathophysiology of ALS matters because the mechanisms underlying each of these stages are probably different. […] The multistep hypothesis for disease pathogenesis provides a fairly good idea regarding how and where ALS is initiated. […] In summary, our current understanding of ALS pathogenesis is sufficiently advanced, that it is time to retire the adage the cause of ALS is unknown. It is more correct to say that we have a fairly good understanding of how ALS is initiated and how it spreads, new and more specific information is emerging every year, and that this information has led and is leading to clinical trials focusing more directly on the processes involved early in the course of the disease.

• #99 Pathophysiology of Amyotrophic Lateral Sclerosis | IntechOpen

  https://www.intechopen.com/chapters/45326

  SOD1 is primarily an antioxidant metalloenzyme that catalyzes the conversion of superoxide radical (O2.-) to oxygen (O2) and hydrogen peroxide (H2O2). However, SOD1-linked fALS is most likely not caused by loss of the normal SOD1 activity, but rather by a gain of a toxic function. […] One of the hypotheses for mutant SOD-linked fALS toxicity proposes that an aberrant SOD1 chemistry is responsible for the toxic gain-of-function, which allows small molecules such us peroxynitrite or hydrogen peroxide to produce damaging free radicals. […] Other hypotheses for mutant SOD1 neurotoxicity include inhibition of the proteasome activity, mitochondrial damage, and formation of intracellular aggregates. […] SOD1 aggregation is an early event in ALS and could mediate motor neuron degeneration via sequestration of cellular components, decreasing chaperone activity and the ubiquitin proteasome pathway.

• #100 Why do motor neurons degenerate? Actualisation in the pathogenesis of amyotrophic lateral sclerosis | Neurología (English Edition)

  https://www.elsevier.es/en-revista-neurologia-english-edition-495-articulo-why-do-motor-neurons-degenerate-S2173580817301633

  Some studies including patients with this expansion have shown that their levels of C9ORF72 mRNA were up to 50% lower, which suggests that the mutant allele is probably unable to produce mature RNA; this would be linked to the hypothesis of a loss-of-function process. […] In addition to the damage it causes directly, oxidative stress promotes other pathogenic mechanisms which contribute to neuronal alterations, including excitotoxicity, protein aggregation, ER stress response, and mitochondrial dysfunction, and it also affects the interaction between motor neurons and the neuronal microenvironment. […] Although motor neuron degeneration and loss is the main finding in patients with ALS, the condition has also been associated with activation of a neuroinflammatory response. […] This inflammatory response contributes to the progressive degeneration and phenotypic alteration of motor neurons, starting with the first manifestations of the disease.

• #101 New insights into the pathogenesis of amyotrophic lateral sclerosis

  https://medicalxpress.com/news/2024-08-insights-pathogenesis-amyotrophic-lateral-sclerosis.html

  New insights into the pathogenesis of amyotrophic lateral sclerosis […] The metabolism of glucose in the brain is altered in people with a specific ALS-linked genetic mutation, called C9-NRE, and this change occurs many years before the onset of muscle weakening that characterizes the disease. […] Neuronal dysfunction, in turn, further undermines energy pathways in a vicious cycle of stress responses. This feedforward loop of problems that the researchers observed in cell culture and in animal models likely plays a role in the neurodegeneration seen in ALS patients. […] In carefully teasing out the molecular pathways involved, Dr. Trotti says he hopes to identify potential therapeutic targets whereby a drug might interrupt the chain reaction. The idea is to prevent the triggering event and hopefully stave off or slow down disease progression in patients with the genetic mutation. […] Dr. Trotti has hope for medications that are prescribed for diabetes, a condition that also involves altered glucose metabolism. Testing such drugs in preclinical models is the next step to see if they correct the metabolic imbalance.

• #102 Environmental insults: critical triggers for amyotrophic lateral sclerosis | Translational Neurodegeneration | Full Text

  https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-017-0087-3

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by a rapid loss of lower and upper motor neurons. As a complex disease, the ageing process and complicated gene-environment interactions are involved in the majority of cases. […] We propose a new ALS model which links the current knowledge of genetic factors, ageing and environmental insults. This model provides a mechanism as to how ALS is initiated, with environmental insults playing a critical role. […] The available evidence has suggested that inherited defect(s) could cause mitochondrial dysfunction, which would establish the primary susceptibility to ALS. Further study of the underlying mechanism may shed light on ALS pathogenesis. Environmental insults are a critical trigger for ALS, particularly in the aged individuals with other toxicant susceptible genes. The identification of ALS triggers could lead to preventive strategies for those individuals at risk.

• #103 Environmental insults: critical triggers for amyotrophic lateral sclerosis | Translational Neurodegeneration | Full Text

  https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-017-0087-3

  A gene-time-environment model has been proposed, in which environmental risks and ageing interact with a pre-existing genetic load, followed by an unknown mechanism of self-perpetuating decline to death. […] The primary defect is an inherited mitochondrial genetic abnormality, either from the nuclear genome-coded or mitochondrial genes. […] Environmental insults, particularly in the presence of genetic susceptibilities to toxicants, would further damage the mitochondria and trigger the decompensation process in motor neurons. […] Much evidence implicates mitochondrial dysfunction in ALS. […] The finding that mitochondria can be transferred from astrocytes to neurons supports the critical role of mitochondria in neurons, and the possible involvement of astrocytes in ALS pathogenesis.

• #104 Environmental insults: critical triggers for amyotrophic lateral sclerosis | Translational Neurodegeneration | Full Text

  https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-017-0087-3

  A gene-time-environment model has been proposed, in which environmental risks and ageing interact with a pre-existing genetic load, followed by an unknown mechanism of self-perpetuating decline to death. […] The primary defect is an inherited mitochondrial genetic abnormality, either from the nuclear genome-coded or mitochondrial genes. […] Environmental insults, particularly in the presence of genetic susceptibilities to toxicants, would further damage the mitochondria and trigger the decompensation process in motor neurons. […] Much evidence implicates mitochondrial dysfunction in ALS. […] The finding that mitochondria can be transferred from astrocytes to neurons supports the critical role of mitochondria in neurons, and the possible involvement of astrocytes in ALS pathogenesis.

• #105 Environmental insults: critical triggers for amyotrophic lateral sclerosis | Translational Neurodegeneration | Full Text

  https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-017-0087-3

  Environmental insults could further affect the mitochondria, particularly in the presence of susceptibility alleles of the interacting genes, and trigger the decompensation process in ALS susceptible individuals. […] This proposed model could explain the well-known clinical and pathological pattern of ALS starting in one CNS region and spreading to other adjacent region. […] The proposed model emphasises gene-environment interactions, which involves multiple steps. Some crucial environmental insults might have arisen in early development, which makes them difficult to identify.

• #106

  https://journals.lww.com/nrronline/fulltext/2024/05000/pathological_mechanisms_of_amyotrophic_lateral.32.aspx

  Neuroinflammation has been suggested to play a key role within ALS disease onset and progression. […] Activated microglia can activate astrocyte neurotoxicity by secreting inflammatory factors. […] Impaired proteostasis: Aggregated pathological proteins can accumulate in the cytoplasm in large quantities. […] Oxidative stress has been thought to be the initiating factor of ALS and is strongly associated with mitochondrial dysfunction. […] Glutamate excitotoxicity: Glutamate receptor hyperstimulation may occur through several mechanisms, which include increased synaptic glutamate release, altered AMPARs, and decreased clearance of glutamate by astrocytes. […] Defective axonal transport is probably related to the ALS development. […] The UPR crosstalk with mitochondria has been shown to control programmed cell death.

• #107 The pathophysiology of amyotrophic lateral sclerosis (ALS) and the role of C9orf72

  https://www.linkedin.com/pulse/pathophysiology-amyotrophic-lateral-sclerosis-als-role-hoffman

  Morphological and ultrastructural deformities of mitochondria have been found in autopsies of patients with ALS. […] The correlation between ALS and pesticide exposure has been investigated in several studies. […] The C9orf72 gene is so special, because it lies in an intronic region and is transcribed, although normally only exons are transcribed, not introns. […] ALS has been related to the loss-of-function of the C9orf72 gene, gain-of-function of the C9orf72 gene via RNA repeats, gain-of-function via DPR protein, and finally the formation of G-quadruplexes. […] The manner of action in ALS is by way of sequestration of essential RNA-binding proteins into aggregates of repeat containing RNA foci, in the nucleus of the affected cell. […] The final genetical mechanism in ALS involves G-quadruplexes. The C9orf72 hexanucleotide repeat expansions DNA and RNA set up the formation of G-quadruplexes.

• #108 ALS Pathogenesis and Therapeutic Approaches: The Role of Mesenchymal Stem Cells and Extracellular Vesicles

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5359305/

  The main pathogenetic mechanisms involved in motoneuron degeneration in ALS and the main therapeutic strategies proposed to date are here summarized. […] The increasing attention to the use of exosomes for the treatment of neurodegenerative diseases derives from the capability of exosomes to cross the BBB, the physiological barrier that separates the brain parenchyma from circulating blood in the CNS. […] The evaluation of the exosomes content, in terms of proteins, mRNAs and miRNAs, and their correlation with a specific cellular pathway involved in ALS, could pave the way to explain their mechanism of action.

• #109 Akava Therapeutics, Inc. shares recent data suggesting that AKV9 acts on a common mechanism involved in both Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS) | Morningstar

  https://www.morningstar.com/news/business-wire/20250502201698/akava-therapeutics-inc-shares-recent-data-suggesting-that-akv9-acts-on-a-common-mechanism-involved-in-both-alzheimers-disease-ad-and-amyotrophic-lateral-sclerosis-als

  Akava Therapeutics, Inc. shares recent data suggesting that AKV9 acts on a common mechanism involved in both Alzheimers disease (AD) and amyotrophic lateral sclerosis (ALS. […] AKV9 is a protein aggregation inhibitor discovered by Northwestern researchers that was previously shown to improve the health of upper motor neurons that degenerate in ALS. […] In mouse models of ALS having either mutant SOD1 toxicity or TDP-43 pathology, AKV9 was shown to improve the function of diseased upper motor neurons through multiple mechanisms of action. […] The Investigational New Drug application using AKV9 for the treatment of ALS has been cleared by the FDA to proceed with clinical trials.

• #110 NeuroVoices: Brian Lin, PhD, on Targeted Therapies and Biomarkers to Drive New Momentum in ALS Research

  https://www.neurologylive.com/view/neurovoices-brian-lin-targeted-therapies-biomarkers-drive-new-momentum-als-research

  Despite extensive research, amyotrophic lateral sclerosis (ALS) remains a progressive and fatal neurodegenerative disease with limited therapeutic options for patients living with the condition. […] One of the major challenges for the ALS field has been the incomplete understanding of the diseases underlying biology, which has restricted the ability to target upstream mechanisms. […] Studies have also shown that while most ALS treatments are initiated late in the disease course, genetic forms of the disease present a potentially unique opportunity for earlier and more targeted care interventions. […] Tofersen (Qalsody; Biogen) is an FDA-approved antisense oligonucleotide (ASO) treatment for ALS designed to reduce production of superoxide dismutase 1 (SOD1) protein by degrading SOD1 mRNA.

• #111 NeuroVoices: Brian Lin, PhD, on Targeted Therapies and Biomarkers to Drive New Momentum in ALS Research

  https://www.neurologylive.com/view/neurovoices-brian-lin-targeted-therapies-biomarkers-drive-new-momentum-als-research

  Investigators noted that ATLAS represents the first interventional trial in presymptomatic ALS and has the potential to produce critical insights for trials, identification of at-risk individuals, and future treatment paradigms in ALS. […] Lin also emphasized the importance of the ATLAS study evaluating early intervention with tofersen in presymptomatic individuals, and the expanding role of gene therapy platforms, including CRISPR-based technologies. […] Right now, I would say the most promising areas in ALS research are probably the gene-targeted and RNA-targeted therapies, and also biomarker discovery. […] ASOs are really the standouts in the ALS field right now, with tofersen which was approved in 2023. […] For the ALS community, this is really exciting because for the first time, its showing that, at least for the genetic forms of ALS, this disease is treatable.

• #112 VectorY Therapeutics to Present Preclinical Data on Novel ALS Therapeutic Strategy at Target ALS Conference in Boston

  https://www.businesswire.com/news/home/20250507576427/en/VectorY-Therapeutics-to-Present-Preclinical-Data-on-Novel-ALS-Therapeutic-Strategy-at-Target-ALS-Conference-in-Boston

  ~ New data show AAV-delivered antibody fragments targeting oxidized phosphatidylcholines (PC-OxPL), a species of oxidized phospholipids, thereby neutralizing TDP-43 pathology and motor neuron toxicity in ALS models ~ […] ~ Underscores potential of VTx-001 to act on upstream drivers of ALS ~ […] “These findings support our hypothesis that PC-OxPL molecules are a key mediator of ALS pathology, acting upstream of TDP-43 proteinopathy and motor neuron toxicity,” said Sander van Deventer, M.D., Ph.D., president of research and development at VectorY. […] The data underscore the potential of VTx-001 to neutralize upstream pathological drivers in amyotrophic lateral sclerosis (ALS), including oxidized phosphatidylcholines (PC-OxPL), which have been implicated in triggering ALS hallmark TDP-43 proteinopathy and motor neuron degeneration.

• #113 VectorY Therapeutics to Present Preclinical Data on Novel ALS Therapeutic Strategy at Target ALS Conference in Boston

  https://www.businesswire.com/news/home/20250507576427/en/VectorY-Therapeutics-to-Present-Preclinical-Data-on-Novel-ALS-Therapeutic-Strategy-at-Target-ALS-Conference-in-Boston

  PC-OxPL exposure of iPSC-derived motor neurons induced an ALS-like transcriptome, significant TDP-43 pathology, and motor neuron death. […] In VectorY’s preclinical data presented at the conference, VTx-001, an AAV-delivered, single-chain antibody fragment was shown to: Neutralize PC-OxPL-induced TDP-43 pathology […] “VTx-001 offers a novel and complementary mechanism of action – to our lead candidate, VTx-002, which directly targets TDP-43 and for which we anticipate filing an IND before the end of this year.” […] Amyotrophic lateral sclerosis (ALS), a motor neuron disease (MND) also known as Lou Gehrig disease, is a rare neurodegenerative disease characterized by the rapid and progressive loss of motor neurons, leading to paralysis, and death due to the inability to breathe. […] ALS is a fatal disease, with most individuals dying from complications such as respiratory failure within 3 to 5 years of diagnosis, though some may survive longer.

• #114 NeuroVoices: Brian Lin, PhD, on Targeted Therapies and Biomarkers to Drive New Momentum in ALS Research

  https://www.neurologylive.com/view/neurovoices-brian-lin-targeted-therapies-biomarkers-drive-new-momentum-als-research

  I think biomarkers are one of the areas that have seen significant growth in research over the last few years. […] Overall, thats huge for ALS. […] We now have a biomarker called neurofilaments, which can help us track how the disease is progressing in real time. […] This is a marker of neuronal damage, and we can see this marker in the biofluids of patients, like their blood and cerebrospinal fluid. […] Now, its used throughout ALS clinical trials to really track how patients are doing. […] These could potentially revolutionize how we track disease progression in ALS clinical trials, especially for a patient population that cant make it to the clinic at all times. […] This study is particularly exciting because itll tell us a lot about not only whether we can treat disease, but if were able to delay or even prevent ALS from happening in those patients who are genetically predisposed.

• #115 Prilenia partners with Ferrer to advance pridopidine for ALSEnvelope icon

  https://alsnewstoday.com/news/prilenia-enters-into-a-collaboration-and-license-agreement-with-ferrer-for-the-commercialization-and-co-development-of-pridopidine-in-europe-and-other-select-markets/

  Pridopidine is an oral small molecule designed to activate a protein involved in crucial processes needed for the functioning and survival of neurons, or nerve cells. It regulates a number of mechanisms that protect from ALS progression, including the clearance of toxic molecules and energy production, while reducing cellular stress and inflammation. […] In ALS, the companies are planning the launch of a pivotal Phase 3 trial involving people with the motor neuron disease. That comes after encouraging results from the HEALEY ALS Platform Trial (NCT04297683), which showed that pridopidine may slow disease progression and extend survival in individuals with early ALS. […] While the trial failed to meet its primary and secondary goals of slowing disease progression and showing changes in muscle strength, lung function, and survival, a subgroup of patients with early ALS seemed to benefit from the therapy.

• #116 Mechanism that causes ALS nerve destruction unveiled for first time

  https://www.drugtargetreview.com/news/100292/mechanism-that-causes-als-nerve-destruction-unveiled-for-first-time/

  This discovery can lead to the development of new therapies that could either dissolve the TDP-43 protein condensates or increase the production of proteins essential to mitochondrial function, and thereby heal the nerve cells before the irreversible damage that occurs in the spinal cord. […] And if in the future we could diagnose and intervene early enough, maybe it will be possible to inhibit the destructive degeneration in ALS patients muscles.

• #117 Transmission of ALS pathogenesis by the cerebrospinal fluid | Acta Neuropathologica Communications | Full Text

  https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-020-00943-4

  To test the hypothesis that the cerebrospinal fluid (CSF) could provide a spreading route for pathogenesis of amyotrophic lateral sclerosis (ALS), we have examined the effects of intraventricular infusion during 2 weeks of pooled CSF samples from sporadic ALS patients or control CSF samples into transgenic mice expressing human TDP43WT which do not develop pathological phenotypes. […] Infusion of ALS-CSF, but not of control CSF, triggered motor and cognitive dysfunction, as well as ALS-like pathological changes including TDP43 proteinopathy, neurofilament disorganization and neuroinflammation. […] We conclude that the CSF from sporadic ALS contains factors that can transmit and disseminate disease including TDP43 proteinopathy into appropriate recipient animal model expressing human TDP43.

• #118 Transmission of ALS pathogenesis by the cerebrospinal fluid | Acta Neuropathologica Communications | Full Text

  https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-020-00943-4

  It has been proposed that key toxic factors in the spread of ALS disease reside in the cerebro-spinal fluid (CSF). […] Indeed, CSF samples from ALS patients exhibited altered proteome when compared to CSF from healthy controls with potential pathogenicity of the altered components. […] To test the hypothesis that CSF constitutes a route of ALS dissemination including TDP43 pathology, we have performed chronic intracerebroventricular infusion of pooled CSF samples from sporadic ALS patients or from non-ALS control samples into transgenic mice expressing human TDP43WT which do not develop pathological phenotypes. […] Here, we report that a 14-day-infusion of ALS-CSF in hTDP43WT mice triggered motor and cognitive dysfunction as well as ALS-like pathological changes, including cytoplasmic TDP43 proteinopathy, neurofilament abnormalities and neuroinflammation.

• #119 Advances and challenges in understanding the multifaceted pathogenesis of amyotrophic lateral sclerosis

  https://smw.ch/index.php/smw/article/download/1990/2861?inline=1

  Several cytotoxic mechanisms have been described for C9ORF72 hexanucleotide repeat expansions and their relative contribution to ALS pathogenesis is currently under investigation. […] The physiological function of a protein is often linked to a unique structure and stable three-dimensional conformation, as a result of a normal folding pathway. Some proteins can gain toxic properties upon a disturbance of their structure that can stably exist and be transferred to homologous proteins if their structure allows this pathological conformation. This mechanism underlies the pathogenesis of prion diseases, and is suggested to contribute to the progression of many neurodegenerative diseases, such as Alzheimers and Parkinsons diseases. […] The aggregation properties of TDP-43 and FUS are associated with their physiological role in the formation of stress granules. […] All above mechanisms may contribute to C9ORF72 disease and the spreading of TDP-43 pathology in patients with hexanucleotide repeat expansions. […] In conclusion, ALS is complex and heterogeneous disease that is caused by many, seemingly diverse, upstream events.

• #120

  https://journals.lww.com/nrronline/fulltext/2024/05000/pathological_mechanisms_of_amyotrophic_lateral.32.aspx

  Studies indicate that a central role in ALS pathogenesis is played by ER stress and aberrant UPR and that activating ER stress-induced autophagy may increase cytotoxicity. […] The majority of evidence indicates that neurodegeneration induced by C9ORF72 HRE is largely dependent upon the mechanism of toxic acquisition. […] The specific pathogenic mechanisms of ALS remain unresolved after many years of research, the pathophysiological mechanisms of the disease may be due to a combination of mechanisms mediated via complicated interactions among molecular and genetic pathways rather than a single factor.

• #121 ALS Pathogenesis and Therapeutic Approaches: The Role of Mesenchymal Stem Cells and Extracellular Vesicles

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5359305/

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive muscle paralysis determined by the degeneration of motoneurons in the motor cortex brainstem and spinal cord. The ALS pathogenetic mechanisms are still unclear, despite the wealth of studies demonstrating the involvement of several altered signaling pathways, such as mitochondrial dysfunction, glutamate excitotoxicity, oxidative stress and neuroinflammation. […] The involvement of different mechanisms in ALS pathogenesis underlines the need for a therapeutic approach targeted to multiple aspects. […] The identification of molecular mechanisms by which motoneurons degenerate in ALS is crucial for understanding disease progression and for the development of new therapeutic approaches. Although SOD1 mutations have been linked to ALS since more than two decades, the mechanisms underlying the mode of action of mutant SOD1 and the subsequent neurodegeneration/neurotoxicity are still unclear. Several hypotheses have been proposed in this regards and it seems likely that the combination of mechanisms, rather than a single mechanism, contributes to neurodegeneration in ALS, pointing to a multifactorial pathogenesis.

• #122 Amyotrophic Lateral Sclerosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK556151/

  Amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, is the most common motor neuron disease (MND) in a group of illnesses that involve both upper and lower motor neurons. ALS is a progressive neurodegenerative disorder that causes motor neuron degeneration and death, resulting in muscle weakness and respiratory failure. […] With both sporadic and familial forms, a single and precise etiology of amyotrophic lateral sclerosis is lacking. There are multiple genetic and environmental proposed causes. ALS is incurable, and treatment focuses on symptom management and addressing family and caregiver stress. […] The etiology of ALS is unknown. Numerous possible genetic and sporadic possibilities are suggested. Amyotrophic lateral sclerosis most commonly begins with signs of LMN degeneration affecting the upper extremity but can also present as UMN or bulbar symptoms. […] A single and precise etiology governing ALS is lacking. The possible mechanisms described in the literature are genetic mutations, oxidative stress, excitotoxicity, mitochondrial and proteasomal dysfunctions, altered synaptic function, disturbed axonal transport, and neuroinflammation. […] It appears that ALS develops as a result of the interaction between both genetic and environmental factors.

• #123 ALS Pathogenesis and Therapeutic Approaches: The Role of Mesenchymal Stem Cells and Extracellular Vesicles

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5359305/

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive muscle paralysis determined by the degeneration of motoneurons in the motor cortex brainstem and spinal cord. The ALS pathogenetic mechanisms are still unclear, despite the wealth of studies demonstrating the involvement of several altered signaling pathways, such as mitochondrial dysfunction, glutamate excitotoxicity, oxidative stress and neuroinflammation. […] The involvement of different mechanisms in ALS pathogenesis underlines the need for a therapeutic approach targeted to multiple aspects. […] The identification of molecular mechanisms by which motoneurons degenerate in ALS is crucial for understanding disease progression and for the development of new therapeutic approaches. Although SOD1 mutations have been linked to ALS since more than two decades, the mechanisms underlying the mode of action of mutant SOD1 and the subsequent neurodegeneration/neurotoxicity are still unclear. Several hypotheses have been proposed in this regards and it seems likely that the combination of mechanisms, rather than a single mechanism, contributes to neurodegeneration in ALS, pointing to a multifactorial pathogenesis.

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