Materiały źródłowe

• #1 Spinal muscular atrophy: mechanisms and therapeutic strategies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2875050/

  Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder and a leading genetic cause of infantile mortality. SMA is caused by mutation or deletion of Survival Motor Neuron-1 (SMN1). The clinical features of the disease are caused by specific degeneration of -motor neurons in the spinal cord, leading to muscle weakness, atrophy and, in the majority of cases, premature death. A highly homologous copy gene (SMN2) is retained in almost all SMA patients but fails to generate adequate levels of SMN protein due to its defective splicing pattern. The severity of the SMA phenotype is inversely correlated with SMN2 copy number and the level of full-length SMN protein produced by SMN2 (10-15% compared with SMN1). The precise SMN-associated function that is abrogated in SMA is currently controversial; however, two principal hypotheses have developed: (i) SMN performs an axonal-specific function potentially involving mRNA transport, such as -actin; or (ii) SMA is caused by decreased SMN activity in snRNP biogenesis, and presumably, motor neurons are especially vulnerable to SMN-dependent snRNP perturbations.

• #2 Molecular Pathogenesis and New Therapeutic Dimensions for Spinal Muscular Atrophy

  https://www.mdpi.com/2079-7737/11/6/894

  Molecular Pathogenesis and New Therapeutic Dimensions for Spinal Muscular Atrophy […] The condition known as 5q spinal muscular atrophy (SMA) is a devastating autosomal recessive neuromuscular disease caused by a deficiency of the ubiquitous protein survival of motor neuron (SMN), which is encoded by the SMN1 and SMN2 genes. It is one of the most common pediatric recessive genetic diseases, and it represents the most common cause of hereditary infant mortality. After decades of intensive basic and clinical research efforts, and improvements in the standard of care, successful therapeutic milestones have been developed, delaying the progression of 5q SMA and increasing patient survival. At the same time, promising data from early-stage clinical trials have indicated that additional therapeutic options are likely to emerge in the near future. Here, we provide updated information on the molecular underpinnings of SMA; we also provide an overview of the rapidly evolving therapeutic landscape for SMA, including SMN-targeted therapies, SMN-independent therapies, and combinational therapies that are likely to be key for the development of treatments that are effective across a patient’s lifespan.

• #3 Spinal Muscle Atrophy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560687/

  Spinal muscular atrophy (SMA) denotes a collection of inherited clinical syndromes causing degeneration of anterior horn cells in the spinal cord with associated destruction of alpha motor cells and presents clinically with characteristic proximal muscle weakness and atrophy. […] Homozygous deletion at 5q13 (the coding region for the survival motor neuron (SMN1) gene) is responsible for 95% of cases of SMA, and after cystic fibrosis is the second most common cause of autosomal recessive inherited related mortality with an estimated incidence of 1 in 6000 to 11000. […] In 95% of cases, SMA results from a homozygous deletion of SMN1 on chromosome 5q13; however, this does not explain how there can be significant clinical heterogeneity in phenotype. […] The answer lies in there being two versions of SMN: 1) telemoeric version (SMN1) 2) centromeric version (SMN2) with individuals varying in the number of copies of SMN2 they possess.

• #4 Spinal Muscle Atrophy: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1264401-overview

  Spinal muscle atrophy (SMA; also known as spinal muscular atrophy) is a rare debilitating autosomal recessive hereditary disease characterized by progressive hypotonia and muscular weakness. The characteristic muscle weakness occurs because of a progressive degeneration of the alpha motor neuron from anterior horn cells in the spinal cord. The weakness is more severe in the proximal musculature than in the distal segments. […] SMA is caused by a mutation in the survival motor neuron (SMN) gene. This gene is normally inactive during the fetal period and allows normal apoptosis in the developing fetus. The gene becomes active in the healthy mature fetus to stabilize the neuronal population. […] In a healthy person, this gene produces a protein that is critical to the function of the nerves that control our muscles; without it, those nerve cells cannot properly function and eventually die, leading to debilitating and often fatal muscle weakness. In the absence of the gene, programmed cell death persists. The mechanism and timing of abnormal motor neuron death remain unknown.

• #5 Spinal Muscle Atrophy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560687/

  SMN1 transcription produces a functionally complete mRNA, that can then be encoded to create the SMN protein. […] SMN2 transcription results in functionally complete mRNA 10 to 15% of the time, resulting in far fewer SMN protein being encoded than SMN1. […] SMN2 is identical to SMN1 except for a single C-T substitution in exon 7. […] This truncated mRNA causes similarly truncated non-functional proteins. […] Patients with SMA are lacking SMN1 and are therefore dependent on residual SMN2 production of functional SMN protein for alpha motor neuron function and subsequent survival. […] There is, therefore, a positive correlation seen between the number of copies of SMN2 and phenotype severity with SMA type 1 typically having 1 to 2 copies of SMN2 and SMA type 4 having 3 to 5 SMN2 copies.

• #6 Spinal Muscular Atrophy: The Past, Present, and Future of Diagnosis and Treatment

  https://www.mdpi.com/1422-0067/24/15/11939

  The SMN2 gene primarily produces mRNA lacking exon 7 because the C-to-T transition of SMN2 exon 7 inhibits alternative splicing of exon 7, leading to incomplete inclusion of the exon. The major product of SMN2 is truncated mRNA lacking exon 7, and the minor product is full-length SMN protein from full-length SMN2 mRNA. […] The presence of SMN2 does not fully compensate for the absence of SMN1 in patients with SMA. Although the C-to-T transition in SMN2 is a synonymous mutation, it does not mean that SMN1 and SMN2 work in the same way. SMN1 produces full-length transcripts, and SMN2 primarily produces mRNA lacking exon 7. […] In 2016, nusinersen was the first drug approved for treatment of SMA by the Food and Drug Administration (FDA) in the United States. Two other drugs were subsequently approved by the FDA: onasemnogene abeparvovec and risdiplam.

• #7 Spinal Muscle Atrophy: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1264401-overview

  Patients with SMA have a homozygous deletion of the telomeric SMN gene SMN1, which is found in arm 5q13 (bands q11.2-13.3). This deletion has been demonstrated in as many as 98% of patients with SMA. […] The SMN protein is critical to the health and survival of the nerve cells in the spinal cord that are responsible for muscle contraction (motor neurons). SMN1 has been linked to pre-mRNA splicing, spliceosome biogenesis, and the nucleolar protein fibrillarin. The absence or dysfunction of SMN is reflected by an enhanced neuronal death. […] A second gene also plays a role in producing the SMN protein namely, SMN2, often called the SMA „backup gene.” SMN2 is present in most individuals, including those with SMA. It is almost identical to SMN1, differing only by five nucleotides. Several versions of the SMN protein are produced by SMN2, but only one version (isoform d) is complete and functional. The other proteins produced by SMN2 are more labile and are unable to compensate fully for the absence of SMN1. Thus, only 10-15% of all functional SMN protein is produced from SMN2.

• #8 Spinal muscular atrophy – UpToDate

  https://www.uptodate.com/contents/spinal-muscular-atrophy

  Thus, the loss of the SMN1 protein is partially compensated by SMN2 protein synthesis, a mechanism that explains some but not all of the phenotypic variability in patients with SMA. […] Disease severity in SMA generally correlates inversely with SMN2 copy number, which varies from 0 to 8 in the normal population, and to a lesser degree with the level of SMN protein. […] The presence of four or more copies of SMN2 is associated with a milder phenotype. […] While the most common forms of SMA are caused by deletions or mutations in the SMN1 on chromosome 5q (ie, 5q SMAs), there are many rare non-5q spinal muscular atrophies. […] The non-5q SMAs are genetically and clinically heterogeneous.

• #9 Spinal Muscle Atrophy – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560687/

  The precise role SMN protein plays in neuronal function and development is not fully understood, and its subsequent absence causing such devastating deficits has so far eluded precise pathophysiological descriptions. […] Several hypotheses surrounding SMN protein and its role in SMA exist, two main hypotheses relate to SMN proteins role in 1) The neuronal cytoplasm and 2) the neuronal nucleus. […] SMN protein in the cytoplasm has demonstrated a vital role in mRNA transport through axons, actin dynamics, and vesicle release in the synapse. […] In the nucleus, SMN protein forms small nuclear RNAs (snRNA) and therefore plays a key role in the formation of the spliceosome, which removes introns in pre- mRNA into functional mRNA. […] This explanation hypothesizes the damage motor neurons specifically to either neuronal sensitivity to spliceosome malfunction directly or indirectly through incorrectly spliced mRNA creating dysfunctional proteins key to neuronal function.

• #10 Spinal muscular atrophy (5qSMA): best practice of diagnostics, newborn screening and therapy

  https://www.degruyter.com/document/doi/10.1515/medgen-2020-2033/html?lang=en

  The SMN protein is highly conserved and ubiquitously abundant. Its canonical function is in small nuclear ribonucleoprotein (snRNP) biogenesis and splicing a crucial process for most genes in all cells. […] Low full-length SMN protein levels mainly affect the U12 minor spliceosome and aberrantly spliced transcripts accumulate. […] Alpha-motor neurons in the spinal cord and especially the pre-synapse of the neuromuscular junctions (NMJs) are the mainly affected cell types in SMA. […] Impaired endocytosis, F-actin dynamics and calcium homeostasis are the main underlying cellular mechanisms. […] The lack of development and maturation of NMJs in severe and intermediate SMA types and of maintenance in the mild types are hallmarks of SMA. […] This causes muscle weakness and atrophy of proximal voluntary muscles with an earlier involvement of lower than upper limbs.

• #11 Molecular Pathogenesis and New Therapeutic Dimensions for Spinal Muscular Atrophy

  https://www.mdpi.com/2079-7737/11/6/894

  The majority of 5q SMA cases are caused by an absence of the SMN1 gene. Ninety-five percent of 5q-SMA-affected individuals have a homozygous deletion of SMN1 exon 7 or gene conversion from SMN1 to SMN2, and most of the remaining 5% are compound heterozygotes for an SMN1 exon 7 deletion and an SMN1 point mutation. However, other pathogenic and likely pathogenic variants reported in the SMN1 and SMN2 genes are involved in the 5q SMA types I, II, III, and IV. […] SMN is an RNA-binding protein that performs multiple essential cellular functions and processes, most notably playing a critical role in the small nuclear ribonucleoprotein (snRNP) complex assembly in the cytoplasm. The large SMN complex is involved in the assembly, metabolism, and transport of diverse ribonucleoproteins and is encompassed by the SMN protein and seven additional proteins (Gemin2–8). The SMN complex is a molecular chaperone whose phosphorylation regulates the biogenesis and function of snRNPs that are involved in splicing.

• #12 Spinal muscular atrophy | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-6-71

  Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by degeneration of alpha motor neurons in the spinal cord, resulting in progressive proximal muscle weakness and paralysis. This disease is caused by homozygous mutations of the survival motor neuron 1 (SMN1) gene, and the diagnostic test demonstrates in most patients the homozygous deletion of the SMN1 gene, generally showing the absence of SMN1 exon 7. Loss of SMN1 is essential to the pathogenesis of SMA, while the severity of the disease is primarily related to the number of copies of SMN2. Two main hypothesis have been postulated to explain the pathogenesis of SMA: (a) SMN is involved in the biogenesis of small nuclear ribonucleoproteins (snRNPs) and in mRNA splicing: thus SMN reduction may determine a general perturbation in snRNP assembly (to which motor neurons may be more sensitive), and/or SMN complex is involved in the splicing of one or few transcripts with a key function in motor neurons; or (b) SMN has a motor neuron specific function, independent from snRNPs assembly, such as mRNA transport along the axon. Hypothesis (a) is supported by different experimental evidences: SMN protein is a part of a high molecular weight complex including at least eight other proteins, and it is necessary for proper assembly of Smith class core proteins in the Uridine-rich snRNPs (U snRNP). Although SMN protein is expressed in all somatic cells, why motor neurons of the spinal cord are specifically vulnerable in spinal muscular atrophy is puzzling. Some studies suggest that SMN protein might play a key role in cellular functions unique to motor neurons. Also hypothesis (b) is supported by different lines of evidence: several studies suggest that SMN protein might sustain the survival of motor neurons by allowing normal axonal transport and maintaining the integrity of neuromuscular junctions. Very recently, in a mouse model of SMA it has been observed that morphological changes occurring at early stages of the disease, include reduced proprioceptive reflexes that correlate with decreased number and function of synapses on motor neuron somata and proximal dendrites.

• #13 Unravelling the cellular mechanism of spinal muscular atrophy: from gene and modifiers to therapy

  https://researchfeatures.com/cellular-mechanism-spinal-muscular-atrophy/

  People with SMA have a deficit of a vital protein called survival motor neuron (SMN). SMN is produced by all body cells and is important for their survival. However, motor neurons require fifty times more SMN than any other cell type. […] In rare families, relatives of SMA-affected individuals may have no SMA symptoms despite carrying two absent SMN1 genes together with three or four SMN2 copies, a combination that would usually cause SMA. This suggests there are other factors involved in determining the severity of SMA. […] By using advanced technologies to study the genes and proteins of family members in these SMA-discordant families, Professor Wirth has identified two proteins that act as SMA protective modifiers: Plastin 3 (PLS3) and Neurocalcin Delta (NCALD). […] The protective effects of high PLS3 and low NCALD have been corroborated by Prof Wirths group using animal models of SMA, including mice, worms and zebrafish. Here, high levels of PLS3 or low levels of NCALD were shown to reduce disease symptoms.

• #14 Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy | PLOS Genetics

  https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1006744

  We present evidence showing significant differences in the basal transcriptional profile between vulnerable and disease-resistant MN pools in mice, with the most striking difference being a greater expression of mitochondrial and energy metabolism-related genes in disease-resistant MNs. […] Our analyses revealed an enrichment of mitochondrial genes particularly associated with oxidative phosphorylation, cellular respiration and generation of metabolites and energy in the resistant motor neuron pools, identifying a potential role for ATP-dependent pathways in regulating selective vulnerability of MNs in SMA. […] We hypothesized that those MNs capable of better meeting increased energy demands, especially at the NMJ, were more likely to remain stable during disease progression, for example during energy stress induced by the presence of hypoxia in SMA. […] Our findings suggest that targeting the bioenergetic status of MNs represent one attractive approach to develop such a combinatorial therapy.

• #15 Disease Mechanisms and Therapeutic Approaches in Spinal Muscular Atrophy | Journal of Neuroscience

  https://www.jneurosci.org/content/35/23/8691

  Importantly, due to the intrinsic instability of the 5q chromosomal duplication, multiple copies of SMN2 can be present in the human genome and a higher SMN2 copy number correlates inversely with disease severity. […] The development of various animal models of SMA has been key to defining the cellular and molecular basis of the disease. […] Beyond death of spinal motor neurons, SMA pathology is characterized by additional defects that occur both centrally, at synapses impinging on somata and dendrites of motor neurons, and distally, at the neuromuscular junction (NMJ). […] The NMJ defects include presynaptic neurofilament accumulation, reduced vesicle content, and impaired synaptic transmission, as well as defective postsynaptic acetylcholine receptor clustering and motor endplate development.

• #16 Reduced P53 levels ameliorate neuromuscular junction loss without affecting motor neuron pathology in a mouse model of spinal muscular atrophy | Cell Death & Disease

  https://www.nature.com/articles/s41419-019-1727-6

  Spinal Muscular Atrophy (SMA) is a childhood motor neuron disease caused by mutations or deletions within the SMN1 gene. At endstages of disease there is profound loss of motor neurons, loss of axons within ventral roots and defects at the neuromuscular junctions (NMJ), as evidenced by pathological features such as pre-synaptic loss and swelling and post-synaptic shrinkage. […] Recent reports have also revealed an early upregulation of transcripts associated with the P53 signalling pathway. The relationship between the upregulation of these transcripts and pathology within the motor unit is also unclear. […] We demonstrate that NMJ loss occurs prior to cell body loss, and coincides with the onset of symptoms. The onset of NMJ pathology also coincides with an increase in P53-related transcripts at the cell body.

• #17 Unravelling the cellular mechanism of spinal muscular atrophy: from gene and modifiers to therapy

  https://researchfeatures.com/cellular-mechanism-spinal-muscular-atrophy/

  Using these same animal models, the group also showed that both PLS3 and NCALD protect against SMA by restoring endocytosis a process that is essential for recycling the synaptic vesicles involved in transmission of nerve impulses across the neuromuscular junctions, which is impaired in SMA. […] Having identified PLS3 and NCALD as protective modifiers, Prof Wirths group began to explore whether regulating production of these proteins could be used as a therapeutic strategy to treat SMA. […] The first SMN ASO-based therapy (Spinraza) was recently FDA- and EMA-approved. Since the Wirth group have shown that a low dose of SMN-ASOs in combination with high PLS3 or low NCALD protects against even the most severe type of SMA in mice, regulation of these proteins could be used in combinatorial therapies with Spinraza to increase treatment efficacy.

• #18 Pathogenesis of skeletal muscle lesions in spinal muscular atrophy｜News & Events | CiRA | Center for iPS Cell Research and Application, Kyoto University

  https://www.cira.kyoto-u.ac.jp/e/pressrelease/news/230217-130000.html

  Professor Megumu K. Saito and his colleagues have revealed that SMN, a protein involved in spinal muscular atrophy (SMA), promotes the functional maturation of mitochondria by regulating miRNA expression along with MYOD1 during skeletal muscle differentiation. […] Spinal Muscular Atrophy (SMA) is a congenital neuromuscular disease caused by loss-of-function mutations in the SMN1 gene encoding the survival motor neuron (SMN) protein. […] In this study, the research group investigated the pathogenesis of SMA skeletal muscle lesions using myoblasts established from SMA patients-derived iPS (SMA iPS) cells. […] The research team found that both skeletal muscle cells differentiated from SMN1-deficient iPS cells and SMA iPS cells exhibited decreased mitochondrial oxygen consumption. […] These observations suggest that SMN interacted with DNA to control transcription during differentiation. […] These results suggest that SMN is specifically involved in the transcriptional regulation of MYOD1, miR-1, and miR-206 during skeletal muscle differentiation. […] This study has identified one of the pathogenic mechanisms of skeletal muscle lesions in SMA.

• #19 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20231207/Novel-mechanism-leads-to-motor-neuron-degeneration-in-spinal-muscular-atrophy.aspx

  The lab of Yongchao C. Ma, PhD, at Stanley Manne Children’s Research Institute at Ann Robert H. Lurie Children’s Hospital of Chicago uncovered a novel mechanism that leads to motor neuron degeneration in spinal muscular atrophy (SMA). […] Dr. Ma and team found that in SMA, increased activity of a type of enzyme called cyclin-dependent kinase 5 (Cdk5) causes defective function of mitochondria, which is a powerhouse of the cell and serves as a signaling center for many cell processes. In SMA, the mitochondrial dysfunction contributes to cell death or degeneration of motor neurons, and this occurs before symptoms develop. […] The researchers also demonstrated in mouse models and human induced pluripotent stem cell (iPSC) models of SMA that the mitochondrial dysfunction and motor neuron degeneration can be stopped by a Cdk5 inhibitor. After reducing Cdk5 activity, the mice showed significant improvement in SMA symptoms. […] In our previous research, we established that all patients with SMA have the mitochondrial defect. This means that inhibiting Cdk5 could treat all patients, including children whose SMA subtype makes them ineligible for gene therapy.

• #20 New Target Found for Treatment of Spinal Muscular Atrophy | Lurie Children’s

  https://www.luriechildrens.org/en/news-stories/new-target-found-for-treatment-of-spinal-muscular-atrophy/

  Nowy mechanizm, który prowadzi do degeneracji neuronów ruchowych w rdzeniowym zaniku mięśni (SMA), został odkryty przez laboratorium Yongchao C. Ma, PhD, w Stanley Manne Childrens Research Institute. […] W SMA zwiększona aktywność enzymu zwanego kinazą zależną od cykliny 5 (Cdk5) powoduje wadliwą funkcję mitochondriów, co przyczynia się do śmierci komórek lub degeneracji neuronów ruchowych. […] W badaniach na modelach myszy i ludzkich komórkach macierzystych indukowanych pluripotentnych (iPSC) wykazano, że dysfunkcję mitochondriów i degenerację neuronów ruchowych można zatrzymać za pomocą inhibitora Cdk5. […] W naszej wcześniejszej pracy ustaliliśmy, że wszyscy pacjenci z SMA mają defekt mitochondrialny. […] To oznacza, że inhibicja Cdk5 mogłaby leczyć wszystkich pacjentów, w tym dzieci, których podtyp SMA czyni je niekwalifikującymi się do terapii genowej. […] Obecnie dostępny inhibitor Cdk5 jest zbyt toksyczny, więc chcemy opracować lepszy inhibitor, który będzie bezpieczniejszy i skuteczniejszy.

• #21 Spinal Muscular Atrophy autophagy profile is tissue-dependent: differential regulation between muscle and motoneurons | Acta Neuropathologica Communications | Full Text

  https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-021-01223-5

  Spinal muscular atrophy (SMA) is a neuromuscular genetic disease caused by reduced survival motor neuron (SMN) protein. SMN is ubiquitous and deficient levels cause spinal cord motoneurons (MNs) degeneration and muscle atrophy. Nevertheless, the mechanism by which SMN reduction in muscle contributes to SMA disease is not fully understood. […] Here we propose to evaluate autophagy in SMA muscle, a pathway altered in myotube atrophy. […] Muscle biopsies, fibroblasts, and lymphoblast cell lines from SMA patients showed reduction of the autophagy marker LC3-II. In SMA mouse gastrocnemius, we observed lower levels of LC3-II, Beclin 1, and p62/SQSTM1 proteins at pre-symptomatic stage. mTOR phosphorylation at Ser2448 was decreased in SMA muscle cells. However, in mouse and human cultured SMA MNs mTOR phosphorylation and LC3-II levels were increased. These results suggest a differential regulation in SMA of the autophagy process in muscle cells and MNs.

• #22 Spinal Muscular Atrophy autophagy profile is tissue-dependent: differential regulation between muscle and motoneurons | Acta Neuropathologica Communications | Full Text

  https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-021-01223-5

  These differences may reflect a specific response to SMN reduction, which could imply diverse tissue-dependent reactions to therapies that should be taken into account when treating SMA patients. […] The reduced levels of the autophagosome marker LC3-II in muscle, lymphocytes, and fibroblasts indicate either decreased autophagosomes formation or increased autophagy flux. […] In contrast, at the disease end-point (P5 gastrocnemius) LC3-II was clearly increased in SMA condition, indicating augmented autophagosomes in muscle cells at the final stage of the disease when cells are likely collapsed. […] Our results indicate reduced Ser2448 phosphorylation in SMA mouse gastrocnemius with no modifications of mTOR protein level. […] However, mTOR phosphorylation in isolated SMA mouse and human MNs was significantly increased in these cells, but was reduced in protein extracts from spinal cords. […] These observations may suggest a differential regulation of mTOR phosphorylation in MNs and non-neuronal cells in the context of SMA.

• #23 Notch Signaling Mediates Astrocyte Abnormality in Spinal Muscular Atrophy Model Systems | Scientific Reports

  https://www.nature.com/articles/s41598-019-39788-w

  Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by the degeneration of spinal motor neurons and muscle atrophy. The disease is mainly caused by low level of the survival motor neuron (SMN) protein, which is coded by two genes, namely SMN1 and SMN2, but leads to selective spinal motor neuron degeneration when SMN1 gene is deleted or mutated. […] Previous reports have shown that SMN-protein-deficient astrocytes are abnormally abundant in the spinal cords of SMA model mice. However, the mechanism of the SMN-deficient astrocyte abnormality remains unclear. […] In the present study, we found that the astrocyte density was increased around the central canal of the spinal cord in a mouse SMA model and we identified the dysregulation of Notch signaling which is a known mechanism that regulates astrocyte differentiation and proliferation, in the spinal cord in both early and late stages of SMA pathogenesis. Moreover, pharmacological inhibition of Notch signaling improved the motor functional deficits in SMA model mice. These findings indicate that dysregulated Notch signaling may be an underlying cause of SMA pathology.

• #24 Notch Signaling Mediates Astrocyte Abnormality in Spinal Muscular Atrophy Model Systems | Scientific Reports

  https://www.nature.com/articles/s41598-019-39788-w

  Our results indicate that Notch signaling may be involved in SMA pathogenesis. […] The results of the present study suggest that chronic SMN depletion during developmental stages might cause an abnormal increase in astrocytes in early-onset SMA via Notch signaling dysregulation. In addition, Notch signaling was critically involved in the SMA pathology in a mouse model, indicating that manipulation of the Notch pathway may be a promising approach to treat patients with SMA. […] Taken together, our results suggest that Notch signaling is involved in SMA pathology and might be used as a therapeutic target of SMA treatments.

• #25 Reduced P53 levels ameliorate neuromuscular junction loss without affecting motor neuron pathology in a mouse model of spinal muscular atrophy | Cell Death & Disease

  https://www.nature.com/articles/s41419-019-1727-6

  Together this work provides a detailed temporal description of pathology within motor units of an SMA mouse model, and demonstrates that NMJ loss is a P53-dependant process. This work supports the role for P53 as an effector of synaptic and axonal degeneration in a die-back neuropathy. […] The data presented here demonstrate that knockout of P53 can reduce NMJ loss, and therefore suggest that axon and synaptic degeneration in SMA is a P53-dependant process. […] Importantly, post-natal knockout of P53 led to a reduction in NMJ loss, without affecting other aspects of NMJ pathology, motor neuron loss or affecting the phenotype of the mouse. […] The reduction in P53 levels allows us to more carefully dissect the interdependency of these early events. Reduced P53 levels had no effect on swelling, but did reduce denervation. This shows that pre-synaptic swelling is a P53-independent event, whilst denervation is a P53-dependant event. […] Overall, in the Smn2B/ mouse model, reduced P53 levels do not appear to reduce motor neuron cell body loss or shrinkage.

• #26 Spinal Muscle Atrophy: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1264401-overview

  The severity of SMA is inversely related to the number of copies of SMN2. Most severely affected individuals will have fewer copies of this gene. The SMN2 gene copy number is related to, but not predictive of, disease severity, and care decisions should not be made on the basis of copy number alone. Other genetic modifiers, such as the protein plastin-3 (PLS3), may influence disease severity. […] A significant increase in nuclear DNA vulnerability was detected in fetuses with SMA at 12-15 weeks’ gestational age. This reflected a decrease in the number of anterior horn neurons. This vulnerability is no longer seen in the rest of the antenatal or postnatal period. Abnormal cell morphology was seen only in the postnatal period.

• #27

  https://omim.org/entry/253300

  A number sign (#) is used with this entry because spinal muscular atrophy type I (SMA1) is caused by mutation or deletion in the telomeric copy of the SMN gene, known as SMN1 (600354), on chromosome 5q13. […] Changes in expression of the centromeric copy of SMN, SMN2 (601627), are known to modify the phenotype. […] Oprea et al. (2008) discovered that unaffected SMN1-deleted females exhibit significantly higher expression of plastin-3 (PLS3; 300131) than their SMA-affected counterparts. The authors demonstrated that PLS3 is important for axonogenesis through increasing the F-actin level. Overexpression of PLS3 rescued the axon length and outgrowth defects associated with SMN downregulation in motor neurons of SMA mouse embryos and in zebrafish. Oprea et al. (2008) concluded that defects in axonogenesis are the major cause of SMA, thereby opening new therapeutic options for SMA and similar neuromuscular diseases.

• #28

  https://omim.org/entry/253300

  Wen et al. (2010) described a potential link between stathmin (STMN1; 151442) and microtubule defects in SMA. Stathmin was identified by screening Smn-knockdown NSC34 cells through proteomics analysis. Stathmin was aberrantly upregulated in vitro and in vivo, leading to a decreased level of polymerized tubulin, which was correlated with disease severity. Reduced microtubule densities and beta-3-tubulin (TUBB3; 602661) levels in distal axons of affected SMA-like mice and an impaired microtubule network in Smn-deficient cells were observed, suggesting an involvement of stathmin in those microtubule defects. Furthermore, knockdown of stathmin restored the microtubule network defects of Smn-deficient cells, promoted axon outgrowth, and reduced the defect in mitochondria transport in SMA-like motor neurons. The authors concluded that aberrant stathmin levels may play a detrimental role in SMA.

• #29 Elucidating the Pathogenic Mechanism of Spinal Muscular Atrophy Through the Investigation of UTS2

  https://www.imrpress.com/journal/FBL/30/2/10.31083/FBL28242

  Elucidating the Pathogenic Mechanism of Spinal Muscular Atrophy Through the Investigation of UTS2 […] Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by mutations in the survival motor neuron 1 (SMN1) gene, resulting in progressive motor neuron loss and muscle atrophy. […] Notably, elevated expression levels of UTS2 have been observed in SMA patients. However, its precise contribution to disease pathogenesis remains unclear. […] UTS2 was successfully identified as a highly expressed protein associated with SMA. […] Urantide intervention significantly affected both proliferation and apoptosis in the SMA cell model in a dose-dependent manner. […] We elucidated the role of the UTS2 gene in an SMA cell model, emphasizing its dysregulation and identifying potential therapeutic targets. Urantide, a UTS2 inhibitor, had significant biological effects on the SMA cell model, indicating that it is a promising therapeutic strategy for SMA. These findings provide valuable insights for advancing drug development and clinical treatment of SMA.

• #30 Elucidating the Pathogenic Mechanism of Spinal Muscular Atrophy Through the Investigation of UTS2

  https://www.imrpress.com/journal/FBL/30/2/10.31083/FBL28242/htm

  The observation that urantide treatment significantly influences cell proliferation in SMA cell models is particularly intriguing. […] The observed increase in Caspase-3 expression following urantide treatment suggested that UTS2 may regulate apoptotic pathways in the SMA. […] Our study elucidates the role of UTS2 in SMA and identifies UTS2 as a potential therapeutic target.

• #31 Mechanisms of disease pathogenesis in Spinal Muscular Atrophy

  https://era.ed.ac.uk/handle/1842/9774

  Dysregulation of UBA1 and subsequently the ubiquitination pathways led to the accumulation of -catenin. […] Thus disruption of ubiquitin homeostasis, with downstream consequences for -catenin signalling, contributes to the pathogenesis of SMA, thereby highlighting novel therapeutic targets for this disease.

• #32 Bioenergetic status modulates motor neuron vulnerability and pathogenesis in a zebrafish model of spinal muscular atrophy | PLOS Genetics

  https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1006744

  Degeneration and loss of lower motor neurons is the major pathological hallmark of spinal muscular atrophy (SMA), resulting from low levels of ubiquitously-expressed survival motor neuron (SMN) protein. […] Here, we demonstrate that selective vulnerability of distinct motor neuron pools arises from fundamental modifications to their basal molecular profiles. […] Targeting of identified bioenergetic pathways by enhancing mitochondrial biogenesis rescued motor axon defects in SMA zebrafish. […] We conclude that global bioenergetics pathways can be therapeutically manipulated to ameliorate SMA motor neuron phenotypes in vivo. […] Understanding the mechanisms governing this selective vulnerability could identify candidates for protective modifier therapy development. […] We also show that targeting of bioenergetic genes rescued motor neuron outgrowth defects in a zebrafish SMA model.

• #33

  https://www.croris.hr/crosbi/publikacija/prilog-skup/687024

  The pathogenesis of spinal muscular atrophy (CROSBI ID 687024) […] Although it is known that deletions or mutations of the SMN1 gene on chromosome 5 cause decreased levels of the SMN protein in subjects with proximal autosomal recessive spinal muscular atrophy (SMA), the exact sequence of pathological events leading to selective motoneuron cell death is not fully understood. New findings regarding the dual cellular role of the SMN protein (translocation of beta-actin to axonal growth cones and snRNP biogenesis/pre-mRNA splicing) were integrated with recent data obtained by detailed neuropathological examination of SMA and control subjects. A presumptive series of 10 pathogenetic events for SMA is proposed as follows: (1) deletions or mutations of the SMN1 gene, (2) increased SMN mRNA decay and reduction in full-length functional SMN protein, (3) impaired motoneuron axono- and dendrogenesis, (4) failure of motoneurons to form synapses with corticospinal fibers from upper motoneurons, (5) abnormal motoneuron migration towards ventral spinal roots, (6) inappropriate persistence of motoneuron apoptosis due to impaired differentiation and motoneuron displacement, (7) substantial numbers of motoneurons continuing to migrate abnormally (heterotopic motoneurons) and entering into the ventral roots, (8) attracted glial cells following these heterotopic motoneurons, which form the glial bundles of ventral roots, (9) impaired axonal transport of actin, causing remaining motoneurons to become chromatolytic, and (10) eventual death of all apoptotic, heterotopic and chromatolytic neurons, with apoptosis being more rapid and predominating in the earlier stages, with death of heterotopic and chromatolytic neurons occurring more slowly by necrosis during the later stages of SMA. According to this model, the motoneuron axonopathy is more important for pathogenesis than the ubiquitous nuclear splicing deficit. It is also supposed that individually variable levels of SMN protein, together with influences of other phenotype modifier genes and their products, cause the clinical SMA spectrum through differential degree of motoneuron functional loss.

• #34 The pathogenesis of spinal muscular atrophy – CROSBI

  https://www.bib.irb.hr:8443/1045597

  The pathogenesis of spinal muscular atrophy […] Although it is known that deletions or mutations of the SMN1 gene on chromosome 5 cause decreased levels of the SMN protein in subjects with proximal autosomal recessive spinal muscular atrophy (SMA), the exact sequence of pathological events leading to selective motoneuron cell death is not fully understood. […] A presumptive series of 10 pathogenetic events for SMA is proposed as follows: (1) deletions or mutations of the SMN1 gene, (2) increased SMN mRNA decay and reduction in full-length functional SMN protein, (3) impaired motoneuron axono- and dendrogenesis, (4) failure of motoneurons to form synapses with corticospinal fibers from upper motoneurons, (5) abnormal motoneuron migration towards ventral spinal roots, (6) inappropriate persistence of motoneuron apoptosis due to impaired differentiation and motoneuron displacement, (7) substantial numbers of motoneurons continuing to migrate abnormally (heterotopic motoneurons) and entering into the ventral roots, (8) attracted glial cells following these heterotopic motoneurons, which form the glial bundles of ventral roots, (9) impaired axonal transport of actin, causing remaining motoneurons to become chromatolytic, and (10) eventual death of all apoptotic, heterotopic and chromatolytic neurons, with apoptosis being more rapid and predominating in the earlier stages, with death of heterotopic and chromatolytic neurons occurring more slowly by necrosis during the later stages of SMA. According to this model, the motoneuron axonopathy is more important for pathogenesis than the ubiquitous nuclear splicing deficit. It is also supposed that individually variable levels of SMN protein, together with influences of other phenotype modifier genes and their products, cause the clinical SMA spectrum through differential degree of motoneuron functional loss.

• #35 Molecular Pathogenesis and New Therapeutic Dimensions for Spinal Muscular Atrophy

  https://www.mdpi.com/2079-7737/11/6/894

  Despite major advance in treatment options for 5q SMA, this monogenic disorder remains an incurable disease. Therapeutic strategies have focused on approaches that increase SMN protein expression, such as the modification of SMN2 splicing, the increase of SMN transcripts, and the replacement of defective SMN1, and approaches that are independent of SMN protein, such as neuroprotection, stem cell therapy, muscle enhancement, and the improved function of neuromuscular junction. […] Identification of a genetic deletion in the SMN1 gene in the majority of 5q SMA patients and its resulting decrease in SMN protein provided a rationale for aiming to restore SMN protein levels by manipulating the SMN2 paralogue. Given that exon 7 exclusion from the pre-mRNA SMN2 transcript results in a truncated version of the SMN protein that is degraded, numerous studies elucidated several SMN2-splicing regulation sites within exon 7 and its neighbor introns that have been assessed as potential therapeutic targets to promote exon 7 inclusion.

• #36 Spinal Muscular Atrophy Treatment – Cure SMA

  https://www.curesma.org/spinal-muscular-atrophy-treatment/

  Due to a mutation in the survival motor neuron gene 1 (SMN1), individuals with SMA do not produce survival motor neuron (SMN) protein at high enough levels. Without this protein, the motor neuron cells shrink and eventually die. This causes debilitating and potentially fatal muscle weakness. […] Many SMN-enhancing treatments target the SMN2 gene, causing it to make more useable SMN protein. Other SMN-enhancing approaches work to replace the function of or repair the mutated SMN1 gene. […] Regardless of what type of treatment is selected, it is important that individuals with SMA begin therapy as soon after diagnosis as possible. This is especially critical for SMN-enhancing therapies. When SMN levels are low, motor neuron cells shrink and eventually die. […] Beginning therapy as early as possible is the only way to prevent or slow down motor neuron loss. […] In clinical trials of SMN-based therapies, infants and children who began spinal muscular atrophy treatment earlier had better results than those who began treatment later.

• #37 Spinal Muscular Atrophy

  https://practicalneurology.com/articles/2020-july-aug/spinal-muscular-atrophy-1

  Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder of infancy, childhood, and young adulthood. The cause of SMA is a biallelic homozygous deletion (95%) or other mutation in the survival motor neuron1 (SMN1) gene located on chromosome 5q, which results in degeneration of the anterior horn motor neurons. The SMN2 gene has a single nucleotide difference (C to T transition), generating a truncated protein without exon 7 (delta 7-SMN). The severity of SMA is ameliorated by the number of SMN2 copies an individual has. People with less severe SMA have more copies of SMN2. The SMN2 gene produces only a small amount of full-length SMN mRNA. […] Nusinersen increases the production of full-length SMN protein by promoting the inclusion of exon 7 in the SMN2 mRNA transcript. Nusinersen is a modified antisense oligonucleotide (ASO), designed to target a heterogeneous nuclear ribonucleoprotein (hnRNP)-A1 / A2dependent splicing silencer, ISS-N1, in intron 7 of the SMN pre-mRNA. By displacing the silencer, accurate splicing of SMN2 transcripts is facilitated such that more transcripts containing exon 7 are produced and translated into full-length SMN protein.

• #38 Spinal Muscular Atrophy

  https://practicalneurology.com/articles/2020-july-aug/spinal-muscular-atrophy-1

  Onasemnogene is a 1-time gene-replacement therapy (GRT) designed to deliver a fully functional copy of the human SMN1 gene administered intravenously. The SMN1 gene is delivered on-replicating recombinant adeno-associated virus serotype 9 (AAV9) vector. […] The approval of effective therapies for SMA has completely changed the landscape for SMA, converting a usually terminal early-life diagnosis into a treatable condition. It is likely that a combination of SMN directed and SMN-independent treatments will be the future of SMA treatment.

• #39 Spinal Muscular Atrophy: Classification, Diagnosis, Background, Molecular Mechanism and Development of Therapeutics | IntechOpen

  https://www.intechopen.com/chapters/44574

  However, motor neuron autonomy of SMA pathogenesis has recently been called into question as multi-system involvement (including cardiovascular, peripheral necrosis and liver defects) have been reported recently in both SMA patients and SMA mice models. […] The suppression of exon 7 skipping to produce more full length transcript from the SMN2 gene is another treatment strategy being explored for SMA. […] The most promising compounds which correct splicing by preventing SMN2 exon 7 skipping are antisense oligos (ASOs). […] The major hurdle in using ASOs for SMA therapeutics, however, is their inability to cross the blood brain barrier.

• #40 Unravelling the cellular mechanism of spinal muscular atrophy

  https://researchoutreach.org/articles/unravelling-the-cellular-mechanism-of-spinal-muscular-atrophy-from-gene-and-modifiers-to-therapy/

  Both high PLS3 and low NCALD levels have been shown to protect against disease symptoms. […] Using these same animal models, the group also showed that both PLS3 and NCALD protect against SMA by restoring endocytosis a process that is essential for recycling the synaptic vesicles involved in transmission of nerve impulses across the neuromuscular junctions, which is impaired in SMA. […] Having identified PLS3 and NCALD as protective modifiers, Prof Wirths group began to explore whether regulating production of these proteins could be used as a therapeutic strategy to treat SMA. […] Both approaches dramatically reduced SMA symptoms. […] In this instance, a combined therapy with a second agent, such as PLS3 or NCALD, could constitute a long term therapeutic option. […] Since the Wirth group have shown that a low dose of SMN-ASOs in combination with high PLS3 or low NCALD protects against even the most severe type of SMA in mice, regulation of these proteins could be used in combinatorial therapies with Spinraza to increase treatment efficacy.

• #41 Unravelling the cellular mechanism of spinal muscular atrophy

  https://researchoutreach.org/articles/unravelling-the-cellular-mechanism-of-spinal-muscular-atrophy-from-gene-and-modifiers-to-therapy/

  Prof Wirths research highlights the power of protective modifiers to unveil the cellular mechanisms and develop novel therapies for SMA. […] It is therefore very likely that people with type I SMA and only two SMN2 copies also require more SMN in every single cell and not only in motor neurons to maintain their function lifelong. […] In SMN2 this splicing process is impaired due to one different nucleotide in exon 7. […] For these populations, we will need a combinatorial treatment using the knowledge of our independent protective modifiers.

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