Choroba neuronu ruchowego (chnr) – Patofizjologia i mechanizm

Choroba neuronu ruchowego (chnr)
Patofizjologia i mechanizm

Choroba neuronu ruchowego (CHNR) to grupa przewlekłych zaburzeń neurologicznych charakteryzujących się postępującą degeneracją zarówno górnych, jak i dolnych neuronów ruchowych. Patogeneza obejmuje mutacje w genach takich jak C9ORF72, TARDBP, SOD1 i FUS, które odpowiadają za około 70% przypadków rodzinnego ALS. Uszkodzenie neuronów ruchowych wynika z zaburzeń homeostazy białek, metabolizmu RNA, dysfunkcji mitochondriów, stresu oksydacyjnego oraz zaburzeń transportu pęcherzykowego i naprawy DNA. Kluczową rolę odgrywają defekty w homeostazie białek i metabolizmie RNA, a także nadpobudliwość neuronalna i dysfunkcja aksonalna, prowadzące do odnerwienia mięśni i zaniku mięśniowego. Ekscytotoksyczność glutaminianu, potwierdzona podwyższonymi poziomami glutaminianu w płynie mózgowo-rdzeniowym, jest istotnym mechanizmem patogenetycznym, a leczenie riluzolem i edarawonem wykazuje zdolność do spowolnienia progresji choroby poprzez modulację tych procesów.

Mechanizm patogeniczny choroby neuronu ruchowego (chnr)

Choroba neuronu ruchowego (chnr) to grupa przewlekłych, sporadycznych i dziedzicznych zaburzeń neurologicznych charakteryzujących się postępującą degeneracją neuronów ruchowych. Podstawową cechą patologiczną jest degeneracja zarówno dolnych neuronów ruchowych (komórek rogu przedniego rdzenia kręgowego i pnia mózgu, które projektują do mięśni) jak i górnych neuronów ruchowych (neuronów, które projektują z kory mózgowej do pnia mózgu i rdzenia kręgowego). Chociaż głównym miejscem uszkodzenia są komórki rogu przedniego i droga korowo-rdzeniowa, udokumentowano również zajęcie innych części układu nerwowego, w tym kory mózgowej, układu autonomicznego, móżdżku i układu pozapiramidowego.¹

Czynniki genetyczne w patogenezie CHNR

Badania wskazują na znaczący udział czynników genetycznych w patogenezie CHNR. Około 10-15% przypadków to forma rodzinna (dziedziczna), podczas gdy pozostałe 85-90% to przypadki sporadyczne bez jasno określonej etiologii.²³ Cztery geny związane są z około 70% przypadków rodzinnego stwardnienia zanikowego bocznego (ALS): C9ORF72, TARDBP, SOD1 i FUS.⁴ Badania rejestrów populacyjnych ALS nadały wiarygodności hipotezie, że choroba powstaje w wyniku złożonego dziedziczenia genetycznego, gdzie różne czynniki środowiskowe wchodzą w interakcję z mutacjami genetycznymi (obecnymi w wariantach ryzyka) poprzez wieloetapowy proces decydujący o wzorcu manifestacji choroby.⁵

W ostatnich latach zidentyfikowano ponad 40 loci genetycznych związanych z różnymi typami CHNR.⁶ Mutacja w genie C9orf72 skutkuje toksycznym zyskiem funkcji zakłócającym metabolizm RNA, utratą funkcji i akumulacją białek powtórzeń dipeptydowych (DPR).⁷ Istnieją również dowody na mechanizm patogenetyczny dwugenowy lub oligogeniczny w niektórych rodzinach z CHNR.⁸

Procesy molekularne w patogenezie CHNR

Uszkodzenie neuronów ruchowych w CHNR wynika z zaburzenia wielu powiązanych ze sobą wewnątrzkomórkowych procesów, które przypisuje się mutacjom genetycznym prowadzącym do:

Zaburzonej homeostazy białek (mutacje SIGMAR 1M, CHMP2B, c9orf72)
Nieprawidłowego metabolizmu RNA (mutacje SETS, FUS, ANG)
Dysfunkcji mitochondriów (mutacje SOD1, CHCHD10, TARDBP)
Zaburzonego transportu pęcherzykowego (mutacje SOD1, ALS2, FIG4)
Upośledzonej naprawy DNA (mutacje NEK1, C21ORF2, SPG11)
Stresu oksydacyjnego (mutacje SOD1, ALS2, TARDBP2)

Wszystkie te czynniki przyczyniają się do rozwoju neurotoksyczności.⁹

Spośród wymienionych procesów, dwa uważane są za kluczowe w etiopatogenezie uszkodzenia neuronów: defekty w homeostazie białek i metabolizmie RNA.¹⁰ Dodatkowo, nadpobudliwość neuronalna i dysfunkcja aksonalna również odgrywają istotną rolę.¹¹ Procesy te prowadzą do utraty zdolności aksonu neuronu ruchowego do utrzymania swoich projekcji, co skutkuje wycofaniem aksonu i ostatecznie odnerwieniem tkanki docelowej.¹²

glutaminianu”>Eksocytotoksyczność i zaburzenia metabolizmu glutaminianu

Jedną z wiodących teorii patogenezy CHNR jest eksocytotoksyczność wywołana przez glutaminian, główny neuroprzekaźnik pobudzający, który może zaburzać wewnątrzkomórkową homeostazę wapnia, prowadząc do śmierci neuronów ruchowych.¹³ Podwyższone poziomy glutaminianu w płynie mózgowo-rdzeniowym oraz nieprawidłowości w transporcie i wychwycie zwrotnym glutaminianu obserwowane w ludzkich tkankach post mortem, jak również w modelach zwierzęcych CHNR, potwierdzają hipotezę eksocytotoksyczności.¹⁴

Badania wykazały, że u niektórych pacjentów występuje nadprodukcja lub nadwrażliwość na glutaminian, co prowadzi do nadmiernej stymulacji komórek nerwowych, skutkującej apoptozą (śmiercią komórki).¹⁵ Lek riluzol, dostępny w ramach refundacji, wykazał w badaniach klinicznych zdolność do wydłużenia przeżycia o kilka miesięcy i może pomóc pacjentom pozostać dłużej w łagodniejszej fazie choroby poprzez hamowanie uwalniania glutaminianu i zmniejszenie eksocytotoksyczności.¹⁶¹⁷

Agregacja białek i ich rola w patogenezie

Charakterystyczną cechą CHNR jest tworzenie się agregatów, czyli nieprawidłowych skupisk białek, które rozwijają się wewnątrz neuronów ruchowych. Występują one w prawie wszystkich przypadkach CHNR i mogą zakłócać normalne funkcjonowanie neuronów ruchowych.¹⁸ Białko TDP-43 jest najczęściej znajdowanym składnikiem tych agregatów. Jest to białko zaangażowane w przetwarzanie instrukcji genetycznych dla komórki poprzez cząsteczkę znaną jako RNA.¹⁹

W większości przypadków CHNR, zarówno sporadycznych jak i rodzinnych nie związanych z mutacją SOD1, białko TDP-43 tworzy charakterystyczne inkluzje cytoplazmatyczne w niektórych komórkach glejowych i pozostałych neuronach.²⁰ Białko to jest usuwane z jego normalnej lokalizacji jądrowej w dotkniętych chorobą komórkach, oprócz tworzenia potencjalnie szkodliwych inkluzji cytoplazmatycznych, co sugeruje, że utrata funkcji jądrowej może również odgrywać rolę w patogenezie.²¹

„Proteinopatie TDP-43” uważa się obecnie za odpowiedzialne za zdecydowaną większość przypadków CHNR/ALS oraz znaczną część przypadków otępienia czołowo-skroniowego (FTD) nie związanych z białkiem tau.²² Identyfikacja mutacji TARDBP i FUS, a także świadomość, że oba te białka wiążące RNA są powiązane, zawęziła centrum uwagi badań nad procesami chorobowymi do metabolizmu RNA.²³

Rozregulowanie transportu aksonalnego

Transport aksonalny, proces, który pozwala komórkom neuronów ruchowych na przemieszczanie komponentów komórkowych wzdłuż aksonu, jest kluczowy dla prawidłowego funkcjonowania neuronów. Badania sugerują, że systemy transportowe w neuronach ruchowych ulegają zakłóceniu w CHNR.²⁴ Gdy nie działają one prawidłowo, neurony ruchowe nie otrzymują już wsparcia i składników odżywczych, które są niezbędne do ich normalnego funkcjonowania.²⁵

Aberrantny transport aksonalny jest jednym z głównych tematów w patogenezie CHNR, w którym „zamieranie wsteczne” dolnego neuronu ruchowego jest następnie przypuszczalnie odpowiedzialne za konsekwentne zajęcie drogi korowo-rdzeniowej, zauważone nawet w przypadkach klinicznie ograniczonych do dolnych neuronów ruchowych.²⁶

Dysfunkcja mitochondriów i stres oksydacyjny

Mitochondria w neuronach ruchowych osób z CHNR mogą nie funkcjonować prawidłowo. Te „elektrownie komórkowe” dostarczają energii niezbędnej do prawidłowego funkcjonowania neuronu. Uszkodzenie systemu energetycznego spowodowane akumulacją białek wewnątrz mitochondriów uniemożliwia regulację produkcji energii wewnątrz komórek.²⁷

Alternatywna hipoteza, dla której istnieją pewne aktualne dane wspierające, sugeruje, że dysfunkcja mitochondrialna działa razem ze stresem oksydacyjnym, powodując nieprawidłową neurodegenerację poprzez uszkodzenie neuronów ruchowych pośredniczone przez wapń.²⁸ Podwyższone poziomy wolnych rodników tlenowych i reaktywnych form tlenu (ROS) mogą prowadzić do uszkodzenia komórek poprzez utlenianie lipidów, białek i DNA.²⁹

Edarawon, drugi z głównych leków stosowanych w leczeniu CHNR, działa poprzez darowanie elektronów, eliminując nadtlenki lipidów i inne reaktywne formy tlenu, w tym rodniki hydroksylowe (•OH) i nadtlenkowe. Te zbiorowe działania edarawonu, w połączeniu z jego zdolnością do przekraczania bariery krew-mózg, mają zapobiegać dalszemu uszkodzeniu neuronów ruchowych w ośrodkowym układzie nerwowym, ograniczając progresję choroby i wydłużając życie pacjentów z CHNR.³⁰

Rola neuronu i mechanizm jego zwyrodnienia

Na poziomie komórkowym, pierwotne miejsce działania patogenu CHNR znajduje się w jądrze komórkowym, a jego głównym efektem jest powodowanie postępującego hamowania syntezy mRNA kierowanej przez DNA poprzez powolną kondensację chromatyny z metabolicznie aktywnej formy rozproszonej do nieaktywnej formy. Inne obserwowane zmiany patologiczne następują jako część niespecyficznego zaniku komórek, który ostatecznie prowadzi do dysfunkcji, śmierci i zaniku komórek.³¹³²

Neurony ruchowe obumierają poprzez degenerację Wallerowską. Śmierć jednego neuronu prowadzi do degeneracji i śmierci aksonalnej. Gdy proces odnerwienia przewyższa proces ponownego unerwienia, pojawiają się objawy kliniczne. Postępujące odnerwienie prowadzi do zaniku całego mięśnia, powodując zanik mięśni (amiotrofię). W miarę jak uszkodzenie rozszerza się na korowe neurony ruchowe, dochodzi do ścieńczenia dróg korowo-rdzeniowych. Te drogi biegną przez boczną i przednią część rdzenia kręgowego. Postępująca utrata włókien prowadzi do gliozy, która czyni drogi twardymi, co pojawia się jako stwardnienie boczne w badaniu autopsyjnym.³³

Rola komórek glejowych i neuroimmunologia

Komórki glejowe są najczęstszym typem komórek w ośrodkowym układzie nerwowym. Wspierają one neurony, pomagają przekazywać informacje między komórkami oraz dostarczają składniki odżywcze i izolację między innymi komórkami wspierającymi neurony ruchowe.³⁴ Jeśli system transportu odpadów staje się zakłócony, może to prowadzić do nagromadzenia toksycznych odpadów, powodując nieprawidłową aktywność komórkową.³⁵

Neuroinflammacja jest coraz częściej uznawana za czynnik przyczyniający się do patogenezy CHNR. Mikroglej, rezydentne komórki odpornościowe mózgu, stają się aktywowane w CHNR i mogą przyczyniać się do uszkodzenia neuronów ruchowych.³⁶ Badania nad rolą układu odpornościowego w CHNR mogą prowadzić do nowych metod leczenia, które spowolnią lub zatrzymają postęp choroby.³⁷

Ponadto, istnieją pewne dowody na autoimmunopatogenezę w CHNR. Wczesne odkrycia czynnika neurotoksycznego przenoszonego przez surowicę u pacjentów z CHNR zostały potwierdzone, a inni badacze zgłosili obecność autoprzeciwciał skierowanych przeciwko czynnikowi wzrostu pochodzącemu z mięśni dla neuronów rdzeniowych.³⁸

Nowe kierunki badań i potencjalne cele terapeutyczne

Badania nad CHNR znajdują się w ekscytującym momencie. Znaczące postępy w zrozumieniu patogenezy choroby i identyfikacji celów terapeutycznych przyciągają bezprecedensowe zainteresowanie przemysłu i prawdziwy optymizm, że ta choroba jest możliwa do leczenia.³⁹

biomarkerów-i-diagnostyka”>Identyfikacja biomarkerów i diagnostyka

Badania biomarkerów zwiększają nasze zrozumienie choroby i identyfikują cele dla nowych podejść terapeutycznych.⁴⁰ Jednym z głównych celów badań jest identyfikacja i walidacja nowych biomarkerów, które mogłyby umożliwić wcześniejsze rozpoznanie i monitorowanie progresji choroby.⁴¹

Identyfikacja konkretnych białek i biomarkerów związanych z CHNR nie tylko rzuca światło na patofizjologię schorzenia, ale także dostarcza potencjalnych celów do interwencji terapeutycznych.⁴² Identyfikacja potencjalnych biomarkerów do wczesnego wykrywania CHNR jest znaczącym przełomem.⁴³

Nowe podejścia terapeutyczne

Bieżące badania koncentrują się na badaniu potencjalnych nowych dróg terapeutycznych.⁴⁴ Jednym z obiecujących kierunków jest terapia genowa, która może korygować lub kompensować mutacje genetyczne odpowiedzialne za niektóre formy CHNR.⁴⁵

Innym obiecującym podejściem jest celowanie w neuroinflammację za pomocą leków immunomodulujących lub terapii, które modulują aktywność mikrogleju.⁴⁶ Zrozumienie roli układu odpornościowego w CHNR może prowadzić do nowych metod leczenia, które spowolnią lub zatrzymają postęp choroby.⁴⁷

Badania nad rolą stresu w zmianach patologicznych CHNR podkreślają znaczenie zarządzania stresem w leczeniu CHNR.⁴⁸ Potencjalne mechanizmy pogorszenia CHNR wywołanego stresem obejmują aktywację osi podwzgórze-przysadka-nadnercza, nieprawidłową aktywację mikrogleju, stres oksydacyjny i akumulację ziarnistości stresowych.⁴⁹

Modele badawcze i zrozumienie mechanizmów choroby

Naukowcy wykorzystują kombinację biologii komórkowej i molekularnej do rozwikłania patogenezy CHNR w próbkach biologicznych pobranych od pacjentów, systemach hodowli komórkowych i modelach zwierzęcych.⁵⁰ Badacze starają się zidentyfikować i zrozumieć podstawowe mechanizmy leżące u podstaw podatności neuronów ruchowych i degeneracji w CHNR, jednocześnie przekładając swoje odkrycia na odpowiednie cele do skutecznej interwencji.⁵¹

Kluczowe pytania badawcze obejmują: Jaka jest fundamentalna przyczyna CHNR? Kiedy zaczyna się podatność neuronu ruchowego w CHNR? Gdzie CHNR powstaje w ośrodkowym układzie nerwowym? Jakie są podstawowe szlaki śmierci komórkowej pośredniczące w utracie neuronów ruchowych w CHNR? Jak wcześnie musimy interweniować z leczeniem w CHNR?⁵²

Leczenie CHNR opiera się głównie na łagodzeniu objawów. Odkrycie nowych celów terapeutycznych, które mogłyby odmienić lub spowolnić postęp choroby, jest głównym celem badań. Rozumiejąc białka zaangażowane we wczesne etapy choroby, badacze mogą opracować terapie celowane, które mają na celu przywrócenie lub ochronę neuronów ruchowych, potencjalnie zatrzymując lub odwracając postęp CHNR.⁵³

Badania nad białkiem DNAJB5 i oksydowanymi fosfolipidami

Niedawne badania zidentyfikowały białko DNAJB5, które jest białkiem opiekuńczym zaangażowanym w proces zwijania białek. Poziomy DNAJB5 znacząco wzrastają przed początkiem CHNR, szczególnie w obszarach mózgu, gdzie inne białko zwane TDP-43 agreguje.⁵⁴ Sugeruje to, że podniesienie poziomu DNAJB5 może reprezentować mechanizm ochronny neuronów do kontrolowania dysfunkcji TDP-43.⁵⁵

Inne obiecujące badania dotyczą oksydowanych fosfatydylocholiny (PC-OxPL), które wydają się być kluczowym mediatorem patologii CHNR, działającym na wcześniejszym etapie niż proteinopatia TDP-43 i toksyczność neuronów ruchowych.⁵⁶ Nowe dane pokazują, że przeciwciała dostarczane przez wektory AAV, celujące w PC-OxPL, neutralizują patologię TDP-43 i toksyczność neuronów ruchowych w modelach CHNR.⁵⁷

Podsumowując, choroba neuronu ruchowego to złożone schorzenie neurologiczne, którego patogeneza obejmuje wiele wzajemnie powiązanych mechanizmów. Obecne badania koncentrują się na zrozumieniu kluczowych procesów, takich jak zaburzenia homeostazy białek, nieprawidłowy metabolizm RNA, dysfunkcja mitochondriów, stres oksydacyjny, neuroinflammacja i zaburzenia transportu aksonalnego. Identyfikacja biomarkerów i rozwój nowych podejść terapeutycznych, w tym terapii genowej i immunomodulacji, oferuje nadzieję na lepsze zarządzanie tą wyniszczającą chorobą w przyszłości.

Kolejne rozdziały

Zapraszamy do dalszego czytania naszego leksykonu.

Wybierz kolejny rozdział z menu poniżej, aby otworzyć nową podstronę kompedium wiedzy i uzyskać szczegółowe informację o leku, substancji lub chorobie.

Materiały źródłowe

#1 Motor Neuron Disease – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK560774/
Motor neuron disease (MND) refers to a group of chronic sporadic and hereditary neurological disorders characterized by progressive degeneration of motor neurons. […] The prognosis of the motor neuron disease depends upon the age at onset and the area of the central nervous system affected. […] Motor neuron disease (MND) is said to be a progressive neurological disorder that presents with both lower motor neurons (anterior horn cells that project from the brainstem and the spinal cord to the muscle) and upper motor neuron signs (neurons that project to the brainstem and spinal cord from higher cortical centers). […] While the anterior horn cell and the corticospinal tract have been shown to be the primary site of involvement, the involvement of other parts of the nervous system (cortical, autonomic, cerebellar, and extrapyramidal system) has also been documented.
#2 Motor neuron disease: The last 12 months
https://www1.racgp.org.au/ajgp/2022/may/the-last-12-months-of-motor-neuron-disease
For the vast majority of patients, MND is sporadic in onset and there is no known cause. For a small percentage (approximately 10%), MND is familial and most commonly autosomal dominant in inheritance. In the modern era, our understanding of the genetics of this familial cohort has grown significantly. Multiple genetic abnormalities have been elucidated and are responsible for two-thirds of familial and 11% of sporadic cases. These include the C9orf72 repeat expansion and SOD1 mutations, with geographical and phenotypic variability.
#3 VectorY Therapeutics to Present Preclinical Data on Novel ALS Therapeutic Strategy at Target ALS Conference in Boston – Pipelinereview
https://pipelinereview.com/vectory-therapeutics-to-present-preclinical-data-on-novel-als-therapeutic-strategy-at-target-als-conference-in-boston/
The vast majority of cases of ALS (90-95%) are categorized as sporadic, meaning they occur without a known cause, while 5-10% are familial, linked to a genetic mutation passed down through families. […] 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.
#4 Motor Neuron Disease – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK560774/
Existing research points towards an underlying genetic basis. […] Four genes are associated with up to 70 percent cases of Familial ALS, namely the C9ORF72, TARDBP, SOD1, and FUS. […] A study of population-based registries of ALS has led a degree of credibility to the hypothesis that ALS follows a complex genetic inheritance, where a variety of environmental factors interact with genetic mutations (present in at-risk variants), through a multistep process that decides the pattern of the disease manifestation. […] Dysregulation of micro RNA and variations in ion channels that predispose to cellular excitotoxicity has also been postulated as the etiology underlying motor neuron disease. […] Motor neuron injury arising as a result of derangement of multiple interlinked intracellular processes that have been attributed to genetic mutations leading to impaired protein homeostasis (SIGMAR 1M, CHMP2B,c9orf72), aberrant RNA metabolism (SETS, FUS, ANG), mitochondrial dysfunction (SOD1, CHCHD10, TARDBP), dysregulated vesicle transport (SOD1, ALS2, FIG4), impaired DNA repair (NEK1, C21ORF2, SPG11), oxidative stress (SOD 1, ALS2, TARDBP2 mutation), which have all been implicated in the development of neurotoxicity.
#5 Motor Neuron Disease – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK560774/
Existing research points towards an underlying genetic basis. […] Four genes are associated with up to 70 percent cases of Familial ALS, namely the C9ORF72, TARDBP, SOD1, and FUS. […] A study of population-based registries of ALS has led a degree of credibility to the hypothesis that ALS follows a complex genetic inheritance, where a variety of environmental factors interact with genetic mutations (present in at-risk variants), through a multistep process that decides the pattern of the disease manifestation. […] Dysregulation of micro RNA and variations in ion channels that predispose to cellular excitotoxicity has also been postulated as the etiology underlying motor neuron disease. […] Motor neuron injury arising as a result of derangement of multiple interlinked intracellular processes that have been attributed to genetic mutations leading to impaired protein homeostasis (SIGMAR 1M, CHMP2B,c9orf72), aberrant RNA metabolism (SETS, FUS, ANG), mitochondrial dysfunction (SOD1, CHCHD10, TARDBP), dysregulated vesicle transport (SOD1, ALS2, FIG4), impaired DNA repair (NEK1, C21ORF2, SPG11), oxidative stress (SOD 1, ALS2, TARDBP2 mutation), which have all been implicated in the development of neurotoxicity.
#6 Genetic testing for monogenic forms of motor neuron disease/amyotrophic lateral sclerosis in unaffected family members | European Journal of Human Genetics
https://www.nature.com/articles/s41431-024-01718-4
Motor neuron disease (MND), also referred to as amyotrophic lateral sclerosis (ALS), is a monogenic disease in a minority of cases, with autosomal dominant inheritance. […] It then lays out the complexities of MND predictive testing, including the genetic landscape characterised by incomplete penetrance, clinical and genetic heterogeneity, and an oligogenic mechanism of pathogenesis in some cases. […] Pathogenic variants in over 40 genes have been associated with development of MND, most of which are inherited in an autosomal dominant pattern, with reduced penetrance. […] Given the large number of potential causal genes, genomic diagnosis of MND requires genome or exome based testing (rather than single gene testing in Huntingtons Disease). […] A polygenic risk score for MND has been constructed from GWAS data, but it only explains a fraction of MND heritability in the studied population.
#7 Genetic testing for monogenic forms of motor neuron disease/amyotrophic lateral sclerosis in unaffected family members | European Journal of Human Genetics
https://www.nature.com/articles/s41431-024-01718-4
The underlying pathomechanism underpinning C9orf72 MND remains elusive but probably involves a combination of toxic gain of function disturbing RNA metabolism, loss of function and dipeptide repeat protein (DPR) accumulation. […] There is evidence that a digenic or oligogenic mechanism of pathogenesis operates in some MND families.
#8 Genetic testing for monogenic forms of motor neuron disease/amyotrophic lateral sclerosis in unaffected family members | European Journal of Human Genetics
https://www.nature.com/articles/s41431-024-01718-4
The underlying pathomechanism underpinning C9orf72 MND remains elusive but probably involves a combination of toxic gain of function disturbing RNA metabolism, loss of function and dipeptide repeat protein (DPR) accumulation. […] There is evidence that a digenic or oligogenic mechanism of pathogenesis operates in some MND families.
#9 Motor Neuron Disease – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK560774/
Existing research points towards an underlying genetic basis. […] Four genes are associated with up to 70 percent cases of Familial ALS, namely the C9ORF72, TARDBP, SOD1, and FUS. […] A study of population-based registries of ALS has led a degree of credibility to the hypothesis that ALS follows a complex genetic inheritance, where a variety of environmental factors interact with genetic mutations (present in at-risk variants), through a multistep process that decides the pattern of the disease manifestation. […] Dysregulation of micro RNA and variations in ion channels that predispose to cellular excitotoxicity has also been postulated as the etiology underlying motor neuron disease. […] Motor neuron injury arising as a result of derangement of multiple interlinked intracellular processes that have been attributed to genetic mutations leading to impaired protein homeostasis (SIGMAR 1M, CHMP2B,c9orf72), aberrant RNA metabolism (SETS, FUS, ANG), mitochondrial dysfunction (SOD1, CHCHD10, TARDBP), dysregulated vesicle transport (SOD1, ALS2, FIG4), impaired DNA repair (NEK1, C21ORF2, SPG11), oxidative stress (SOD 1, ALS2, TARDBP2 mutation), which have all been implicated in the development of neurotoxicity.
#10 Motor Neuron Disease – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK560774/
Out of the processes mentioned above, the two which have been postulated as being central to the etiopathogenesis of the neuronal injury include defects in protein homeostasis and RNA metabolism. […] Neuronal hyperexcitability and axonal dysfunction have also been implicated in the etiopathogenesis. […] These processes lead to the failure of the motor neuron axon in maintaining its projections leading to retraction of the axon and ultimately resulting in denervation of the target.
#11 Motor Neuron Disease – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK560774/
Out of the processes mentioned above, the two which have been postulated as being central to the etiopathogenesis of the neuronal injury include defects in protein homeostasis and RNA metabolism. […] Neuronal hyperexcitability and axonal dysfunction have also been implicated in the etiopathogenesis. […] These processes lead to the failure of the motor neuron axon in maintaining its projections leading to retraction of the axon and ultimately resulting in denervation of the target.
#12 Motor Neuron Disease – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK560774/
Out of the processes mentioned above, the two which have been postulated as being central to the etiopathogenesis of the neuronal injury include defects in protein homeostasis and RNA metabolism. […] Neuronal hyperexcitability and axonal dysfunction have also been implicated in the etiopathogenesis. […] These processes lead to the failure of the motor neuron axon in maintaining its projections leading to retraction of the axon and ultimately resulting in denervation of the target.
#13 Pathology of Motor Neuron Disorders: Definition, Etiology, Epidemiology
https://emedicine.medscape.com/article/2111360-overview
The etiology of sporadic amyotrophic lateral sclerosis (ALS) remains uncertain, however, ALS is considered to be a multifactorial disease that is triggered by a complex interaction of internal factors (eg, genetic susceptibility to different neuronal insults and immunologic alterations) and external factors (eg, environmental variables). […] The key theories proposed to date for the pathogenesis of ALS include glutamate-induced excitotoxicity, oxidative injury, altered mitochondrial function, cytoskeleton alterations, axonal transport dysregulation, neuroinflammation, immunomodulation, and autoimmunity. […] Of these, the leading theory is excitotoxicity induced by glutamate, the major excitatory neurotransmitter, which may disrupt intracellular calcium homeostasis, resulting in motor neuron death.
#14 Faulty brakes: an inhibitory neuronal deficit in the pathogenesis of motor neuron disease | ACNR
https://acnr.co.uk/articles/faulty-brakes-an-inhibitory-neuronal-deficit-in-the-pathogenesis-of-motor-neuron-disease/
Raised levels of CSF glutamate, and abnormalities of glutamate transport and reuptake in human post mortem tissue as well as animal models of MND, underpin an excitotoxic theme of pathogenesis, in which over-stimulation of motor neurons results in eventual calcium-mediated cell death. […] An alternative or contributory mechanism might be a reduction in inhibitory neuronal influences. […] Pioneering in vivo cortical studies in MND employed activation positron emission tomography (PET), observing an extended area of cortical activation in response to a motor task. […] Application of the PET ligand flumazenil confirmed widespread cerebral reductions in Î³-aminobutyric acid (GABA)-A receptor binding in MND, crucially with relative preservation in those with a consistently more slowly progressive familial form of the disease.
#15 Stem Cell Treatment for Motor Neuron Disease MND
https://stemcellthailand.org/therapies/motor-neuron-disease-mnd/
There is evidence that for some patients, an overproduction or hypersensitivity to glutamate occurs, which causes over-excitation of the nerve cells, resulting in apoptosis (cell death). […] Its important to note that familial and sporadic MND symptoms are nearly identical and can only be differentiated on the genetic level. […] Various environmental factors have been identified to lead to neurodegenerative disease. […] The fact that MND can be passed on genetically suggests that single mutations inherited from the parents may sometimes play a much more significant role in developing the condition later in life. […] The typical symptoms of upper motor neuron disease include frequent cramps, recent weight loss, difficulty swallowing, random muscle twitching, excessive muscle wasting or weakness, fatigue, slurred speech, and drastic emotional changes.
#16 Motor neurone disease (MND) | Better Health Channel
https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/motor-neurone-disease
Motor neurone disease (MND) is still incurable, but not untreatable many symptoms can be managed. […] The causes of MND are unknown, but worldwide research includes studies on: exposure to viruses, exposure to certain toxins and chemicals, genetic factors, inflammation and damage to neurons caused by an immune system response, nerve growth factors, growth, repair and ageing of motor neurons. […] Familial (hereditary) MND accounts for about five to 10 percent of cases. Several gene mutations have been identified since 1993, and current research aims to identify further genes linked to MND. […] MND is still incurable, but it is not untreatable, as many symptoms can be managed. The drug riluzole available on the Pharmaceutical Benefits Scheme has been demonstrated in clinical trials to prolong survival by several months and may help people to remain in the milder phase of the disease for longer.
#17 Motor Neurone Disease Breakthroughs | Open Medscience
https://openmedscience.com/motor-neurone-disease-diagnosis-and-future-research-insights/
Motor neurone disease (MND) is a progressive neurodegenerative disorder characterised by the degeneration of motor neurones, which leads to muscle weakness, atrophy, and eventually death. […] MND is characterised by the degeneration of motor neurones in the brain, brainstem, and spinal cord. The precise cause of this neuronal death remains largely unknown, though genetic and environmental factors are believed to contribute. Mutations in several genes, such as SOD1, TARDBP, FUS, and C9orf72, have been implicated in familial forms of MND. These genetic mutations can lead to toxic protein aggregation, oxidative stress, mitochondrial dysfunction, and impaired axonal transport, all of which contribute to motor neurone degeneration. […] Understanding the mechanisms of action of current treatments is crucial for developing more effective therapies. Riluzoleâs ability to inhibit glutamate release and reduce excitotoxicity helps protect motor neurones from premature death. Edaravoneâs antioxidant properties reduce oxidative stress, which is a key factor in the pathogenesis of MND. ASOs work by targeting specific genetic mutations, offering a precision medicine approach that holds promise for treating hereditary forms of the disease.
#18 Motor neurone disease (MND) | NHS inform
https://www.nhsinform.scot/illnesses-and-conditions/brain-nerves-and-spinal-cord/motor-neurone-disease-mnd/
Motor neurone disease (MND) happens when specialist nerve cells in the brain and spinal cord, called motor neurones, stop working properly and die prematurely. This is known as neurodegeneration. […] One known cause of MND is an error in your genes with 20% of cases linked to genetic causes. […] The error in the gene affects the cells ability to perform normally and survive. […] Most experts believe that its a combination of factors that affect either the motor neurones or the cells that support them. […] Aggregates are abnormal clumps of protein that develop inside motor neurones. Theyre found in nearly all cases of MND and may disrupt the normal working of the motor neurones. […] The protein TDP-43 is most commonly found in these aggregates. This is a protein involved in the processing of the genetic instructions for the cell through a molecule known as RNA.
#19 Motor neurone disease (MND) | NHS inform
https://www.nhsinform.scot/illnesses-and-conditions/brain-nerves-and-spinal-cord/motor-neurone-disease-mnd/
Motor neurone disease (MND) happens when specialist nerve cells in the brain and spinal cord, called motor neurones, stop working properly and die prematurely. This is known as neurodegeneration. […] One known cause of MND is an error in your genes with 20% of cases linked to genetic causes. […] The error in the gene affects the cells ability to perform normally and survive. […] Most experts believe that its a combination of factors that affect either the motor neurones or the cells that support them. […] Aggregates are abnormal clumps of protein that develop inside motor neurones. Theyre found in nearly all cases of MND and may disrupt the normal working of the motor neurones. […] The protein TDP-43 is most commonly found in these aggregates. This is a protein involved in the processing of the genetic instructions for the cell through a molecule known as RNA.
#20 Role of Biomarkers in Pathogenesis and Updated Treatment of Motor Neuron Disease: A Review Article
https://www.mathewsopenaccess.com/full-text/role-of-biomarkers-in-pathogenesis-and-updated-treatment-of-motor-neuron-disease-a-review-article
The ubiquitinated protein TDP-43 has distinctive cytoplasmic inclusions in some glial cells and the remaining neurons. […] The protein is removed from its usual nucleus site in afflicted cells in addition to creating potentially hazardous cytoplasmic inclusions, indicating that a nuclear loss of function may also play a role in pathogenesis. […] 'TDP-43 proteinopathies’ are now thought to account for the great majority of ALS cases as well as a sizable part of non-tau FTD cases. […] The identification of TARDBP and FUS mutations, as well as the knowledge that both of these RNA-binding proteins are related, has narrowed the emphasis of the investigation into upstream illness processes to RNA metabolism. […] Therefore, a general theory is that changes have been made to RNA metabolism at the level of mRNA splicing, transport, or translation control. […] Unusual protein aggregation is a key component of pathogenesis. […] Gene alterations that are directly connected to mechanisms for protein degradation are the root cause of a number of unusual forms of ALS.
#21 Role of Biomarkers in Pathogenesis and Updated Treatment of Motor Neuron Disease: A Review Article
https://www.mathewsopenaccess.com/full-text/role-of-biomarkers-in-pathogenesis-and-updated-treatment-of-motor-neuron-disease-a-review-article
The ubiquitinated protein TDP-43 has distinctive cytoplasmic inclusions in some glial cells and the remaining neurons. […] The protein is removed from its usual nucleus site in afflicted cells in addition to creating potentially hazardous cytoplasmic inclusions, indicating that a nuclear loss of function may also play a role in pathogenesis. […] 'TDP-43 proteinopathies’ are now thought to account for the great majority of ALS cases as well as a sizable part of non-tau FTD cases. […] The identification of TARDBP and FUS mutations, as well as the knowledge that both of these RNA-binding proteins are related, has narrowed the emphasis of the investigation into upstream illness processes to RNA metabolism. […] Therefore, a general theory is that changes have been made to RNA metabolism at the level of mRNA splicing, transport, or translation control. […] Unusual protein aggregation is a key component of pathogenesis. […] Gene alterations that are directly connected to mechanisms for protein degradation are the root cause of a number of unusual forms of ALS.
#22 Role of Biomarkers in Pathogenesis and Updated Treatment of Motor Neuron Disease: A Review Article
https://www.mathewsopenaccess.com/full-text/role-of-biomarkers-in-pathogenesis-and-updated-treatment-of-motor-neuron-disease-a-review-article
The ubiquitinated protein TDP-43 has distinctive cytoplasmic inclusions in some glial cells and the remaining neurons. […] The protein is removed from its usual nucleus site in afflicted cells in addition to creating potentially hazardous cytoplasmic inclusions, indicating that a nuclear loss of function may also play a role in pathogenesis. […] 'TDP-43 proteinopathies’ are now thought to account for the great majority of ALS cases as well as a sizable part of non-tau FTD cases. […] The identification of TARDBP and FUS mutations, as well as the knowledge that both of these RNA-binding proteins are related, has narrowed the emphasis of the investigation into upstream illness processes to RNA metabolism. […] Therefore, a general theory is that changes have been made to RNA metabolism at the level of mRNA splicing, transport, or translation control. […] Unusual protein aggregation is a key component of pathogenesis. […] Gene alterations that are directly connected to mechanisms for protein degradation are the root cause of a number of unusual forms of ALS.
#23 Role of Biomarkers in Pathogenesis and Updated Treatment of Motor Neuron Disease: A Review Article
https://www.mathewsopenaccess.com/full-text/role-of-biomarkers-in-pathogenesis-and-updated-treatment-of-motor-neuron-disease-a-review-article
The ubiquitinated protein TDP-43 has distinctive cytoplasmic inclusions in some glial cells and the remaining neurons. […] The protein is removed from its usual nucleus site in afflicted cells in addition to creating potentially hazardous cytoplasmic inclusions, indicating that a nuclear loss of function may also play a role in pathogenesis. […] 'TDP-43 proteinopathies’ are now thought to account for the great majority of ALS cases as well as a sizable part of non-tau FTD cases. […] The identification of TARDBP and FUS mutations, as well as the knowledge that both of these RNA-binding proteins are related, has narrowed the emphasis of the investigation into upstream illness processes to RNA metabolism. […] Therefore, a general theory is that changes have been made to RNA metabolism at the level of mRNA splicing, transport, or translation control. […] Unusual protein aggregation is a key component of pathogenesis. […] Gene alterations that are directly connected to mechanisms for protein degradation are the root cause of a number of unusual forms of ALS.
#24 Motor neurone disease (MND) | NHS inform
https://www.nhsinform.scot/illnesses-and-conditions/brain-nerves-and-spinal-cord/motor-neurone-disease-mnd/
Research suggests that the transport systems in motor neurones become disrupted. […] When they dont work properly the motor neurones no longer receive the support and nutrition they need to function normally. […] One of the neurotransmitters is called glutamate. It excites neurones and one theory is that too much activity through this causes damage to the neurones. […] Mitochondria in the motor neurones of people with MND might not function properly.
#25 Motor neurone disease (MND) | NHS inform
https://www.nhsinform.scot/illnesses-and-conditions/brain-nerves-and-spinal-cord/motor-neurone-disease-mnd/
Research suggests that the transport systems in motor neurones become disrupted. […] When they dont work properly the motor neurones no longer receive the support and nutrition they need to function normally. […] One of the neurotransmitters is called glutamate. It excites neurones and one theory is that too much activity through this causes damage to the neurones. […] Mitochondria in the motor neurones of people with MND might not function properly.
#26 Faulty brakes: an inhibitory neuronal deficit in the pathogenesis of motor neuron disease | ACNR
https://acnr.co.uk/articles/faulty-brakes-an-inhibitory-neuronal-deficit-in-the-pathogenesis-of-motor-neuron-disease/
Motor neuron disease, in its commonest clinical form amyotrophic lateral sclerosis (ALS), is characterised by the degeneration of upper motor neurons (UMNs) of the corticospinal tract (CST) and lower motor neurons (LMNs) of the brainstem nuclei and spinal cord anterior horns. […] To ask âwhat is the cause of MND?â is to underestimate the emerging pathogenic complexity. […] Cytoplasmic inclusions of the ubiquitinated 43 kDa transactive-region DNA-binding protein, TDP-43, superficially appear to be the unifying hallmark for the 95% who have apparently sporadic MND. […] Aberrant axonal transport is one of several major themes in MND pathogenesis, in which an LMN âdying backâ is then presumed to account for the consistent involvement of the CST, noted even in apparently clinically LMN-only cases.
#27 Stem Cell Treatment for Motor Neuron Disease MND
https://stemcellthailand.org/therapies/motor-neuron-disease-mnd/
Some causes for environmental/sporadic MND include: […] Abnormal protein clumps are known as aggregates. These dysfunctional clumps are found in all cases of MND, develop inside the neurons, and disrupt the normal workings of the motor neurons. […] The mitochondria provide energy for the cells, allowing them to work normally. Patients with MND show damage to this system due to the accumulation of proteins inside the mitochondria, causing them to be unable to regulate energy production inside the cells. […] Glial cells are the most common cell type in the central nervous system. They support neurons, help relay information between cells, and provide nutrients and insulation between other supporting motor neuron cells. […] If this waste transportation system becomes disturbed, it can result in a buildup of toxic waste, causing abnormal cell activity.
#28 Pathology of Motor Neuron Disorders: Definition, Etiology, Epidemiology
https://emedicine.medscape.com/article/2111360-overview
An alternative hypothesis for which there are some current supporting data suggests that mitochondrial dysfunction acts with oxidative stress to cause abnormal neurodegeneration via calcium-mediated motor neuron injury. […] The etiology of primary lateral sclerosis (PLS) is unknown, but it may be similar to that proposed for ALS. […] More than 40 genetic loci ascribed to the different types of hereditary spastic paraparesis (HSP) have been identified; however, a clear genetic basis for most HSP types remains uncertain. […] The etiopathogenesis of Brown-Vialetto-Van Laere syndrome and Fazio-Londe disease remains elusive. […] Type I-III spinal muscular atrophy (SMA) is caused by alterations in the survival motor neuron gene (SMN). […] X-linked spinobulbar muscular atrophy (SBMA) is caused by an expansion of a polymorphic tandem CAG repeat in the first exon of the androgen-receptor gene located on chromosome Xq11-q12, which encodes a polyglutamine stretch that may be a substrate for the caspases (cysteine protease cell death executioners).
#29 Edaravone for the Treatment of Motor Neurone Disease: A Critical Review of Approved and Alternative Formulations against a Proposed Quality Target Product Profile
https://www.mdpi.com/1999-4923/16/8/993
The mechanism of action of edaravone in MND, while uncertain, is generally agreed to be associated with its strong antioxidant properties. […] Edaravone by electron donation can eliminate lipid peroxides and other reactive oxygen species (ROS), including hydroxyl (â¢OH) and peroxyl radicals. […] The collective actions of edaravone, paired with its ability to cross the bloodâbrain barrier, are postulated to prevent further damage to the motor neurones in the central nervous system, thereby limiting disease progression and extending the lifespan of MND patients, especially when treatment is initiated soon after first diagnosis. […] The treatment regimen is the same for both the IV and oral formulations, involving an initial treatment cycle of daily dosing for 14 days followed by 14 drug-free days and subsequent cycles requiring 10 days of daily dosing in a 14-day period followed by 14 drug-free days.
#30 Edaravone for the Treatment of Motor Neurone Disease: A Critical Review of Approved and Alternative Formulations against a Proposed Quality Target Product Profile
https://www.mdpi.com/1999-4923/16/8/993
The mechanism of action of edaravone in MND, while uncertain, is generally agreed to be associated with its strong antioxidant properties. […] Edaravone by electron donation can eliminate lipid peroxides and other reactive oxygen species (ROS), including hydroxyl (â¢OH) and peroxyl radicals. […] The collective actions of edaravone, paired with its ability to cross the bloodâbrain barrier, are postulated to prevent further damage to the motor neurones in the central nervous system, thereby limiting disease progression and extending the lifespan of MND patients, especially when treatment is initiated soon after first diagnosis. […] The treatment regimen is the same for both the IV and oral formulations, involving an initial treatment cycle of daily dosing for 14 days followed by 14 drug-free days and subsequent cycles requiring 10 days of daily dosing in a 14-day period followed by 14 drug-free days.
#31 Motor neurone disease: the nature of the pathogenic mechanism
https://pmc.ncbi.nlm.nih.gov/articles/PMC494835/
Evidence is presented which indicates that the initial site of action of the pathogen of motor neurone disease (MND) is the nucleus, and its prime effect is to cause the progressive inhibition of DNA directed mRNA synthesis by the slow condensation of chromatin from a metabolically active diffuse form to an inactive form. The other pathological changes observed follow as part of a nonspecific cell atrophy which leads eventually to dysfunction, death, and disappearance of cells.
#32 Motor neurone disease: the nature of the pathogenic mechanism | Journal of Neurology, Neurosurgery & Psychiatry
https://jnnp.bmj.com/content/37/9/1036
Evidence is presented which indicates that the initial site of action of the pathogen of motor neurone disease (MND) is the nucleus, and its prime effect is to cause the progressive inhibition of DNA directed mRNA synthesis by the slow condensation of chromatin from a metabolically active diffuse form to an inactive form. […] The other pathological changes observed follow as part of a nonspecific cell atrophy which leads eventually to dysfunction, death, and disappearance of cells.
#33 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.
#34 Stem Cell Treatment for Motor Neuron Disease MND
https://stemcellthailand.org/therapies/motor-neuron-disease-mnd/
Some causes for environmental/sporadic MND include: […] Abnormal protein clumps are known as aggregates. These dysfunctional clumps are found in all cases of MND, develop inside the neurons, and disrupt the normal workings of the motor neurons. […] The mitochondria provide energy for the cells, allowing them to work normally. Patients with MND show damage to this system due to the accumulation of proteins inside the mitochondria, causing them to be unable to regulate energy production inside the cells. […] Glial cells are the most common cell type in the central nervous system. They support neurons, help relay information between cells, and provide nutrients and insulation between other supporting motor neuron cells. […] If this waste transportation system becomes disturbed, it can result in a buildup of toxic waste, causing abnormal cell activity.
#35 Stem Cell Treatment for Motor Neuron Disease MND
https://stemcellthailand.org/therapies/motor-neuron-disease-mnd/
Some causes for environmental/sporadic MND include: […] Abnormal protein clumps are known as aggregates. These dysfunctional clumps are found in all cases of MND, develop inside the neurons, and disrupt the normal workings of the motor neurons. […] The mitochondria provide energy for the cells, allowing them to work normally. Patients with MND show damage to this system due to the accumulation of proteins inside the mitochondria, causing them to be unable to regulate energy production inside the cells. […] Glial cells are the most common cell type in the central nervous system. They support neurons, help relay information between cells, and provide nutrients and insulation between other supporting motor neuron cells. […] If this waste transportation system becomes disturbed, it can result in a buildup of toxic waste, causing abnormal cell activity.
#36 Motor Neurone Disease Breakthroughs | Open Medscience
https://openmedscience.com/motor-neurone-disease-diagnosis-and-future-research-insights/
Neuroinflammation is increasingly recognised as a contributing factor in MND pathogenesis. Microglia, the brainâs resident immune cells, become activated in MND and may contribute to motor neurone damage. Targeting neuroinflammation with immunomodulatory drugs or therapies that modulate microglial activity is an area of active research. Understanding the role of the immune system in MND could lead to novel treatments that slow or stop disease progression. […] Abnormal protein aggregation is a hallmark of MND, particularly in ALS, where proteins such as TDP-43 form toxic aggregates within motor neurones. Research is focused on understanding the mechanisms of protein aggregation and misfolding, as well as developing therapeutic strategies to prevent or clear these aggregates. Several approaches are being explored, including small molecules that enhance protein degradation pathways, such as the ubiquitin-proteasome system or autophagy, and immunotherapy targeting misfolded proteins. The goal is to reduce the toxic burden on motor neurones and slow the progression of the disease.
#37 Motor Neurone Disease Breakthroughs | Open Medscience
https://openmedscience.com/motor-neurone-disease-diagnosis-and-future-research-insights/
Neuroinflammation is increasingly recognised as a contributing factor in MND pathogenesis. Microglia, the brainâs resident immune cells, become activated in MND and may contribute to motor neurone damage. Targeting neuroinflammation with immunomodulatory drugs or therapies that modulate microglial activity is an area of active research. Understanding the role of the immune system in MND could lead to novel treatments that slow or stop disease progression. […] Abnormal protein aggregation is a hallmark of MND, particularly in ALS, where proteins such as TDP-43 form toxic aggregates within motor neurones. Research is focused on understanding the mechanisms of protein aggregation and misfolding, as well as developing therapeutic strategies to prevent or clear these aggregates. Several approaches are being explored, including small molecules that enhance protein degradation pathways, such as the ubiquitin-proteasome system or autophagy, and immunotherapy targeting misfolded proteins. The goal is to reduce the toxic burden on motor neurones and slow the progression of the disease.
#38 Autoimmune Involvement in Motor Neurone Disease | SpringerLink
https://link.springer.com/chapter/10.1007/978-1-4684-5302-7_11
The possibility of an autoimmune pathogenesis in motor neurone disease (MND) has been debated for many years with little consensus. However, recent evidence from different sources has served to redirect attention towards such an involvement. Thus, early findings of a serum-borne neurotoxic factor in MND patients have been confirmed by Roisen et al., while Gurney and his colleagues have reported the presence in MND sera of autoantibodies to a muscle-derived growth factor for spinal neurones.
#39 Researching motor neurone disease: highlight notice – UKRI
https://www.ukri.org/opportunity/researching-motor-neurone-disease-highlight-notice/
MND is a devastating neurodegenerative disease, characterised by loss of motor neurone function. In patients suffering with MND, signals from the motor neurones gradually stop reaching the muscles causing them to weaken, stiffen and waste. […] Research on MND is at an exciting juncture. Significant advances in understanding disease pathogenesis and identifying therapeutic targets are attracting unprecedented interest from industry and a genuine optimism that this disease is tractable. […] improve the mechanistic understanding of MND, including identification and validation of new biomarkers […] investigate potential new therapeutic avenues. […] Damage to functions regulated by ER-mitochondria signalling, mediated by VAPB-PTPIP51, is a feature of ALS therefore this work could facilitate the design of potential therapeutics. […] This clinician scientist fellowship investigates changes in metabolism in two mouse models of MND in order to identify common changes that could be used as therapeutic targets.
#40
https://www.jchr.org/index.php/JCHR/article/view/5114
Motor neuron disease (MND) is a severe adult-onset neurodegenerative disorder that most commonly presents as amyotrophic lateral sclerosis (ALS). […] The study of pathophysiological pathways through biomarker research increases our understanding of disease and identifies targets for new therapeutic approaches. […] One of the primary contributions to the development of neuronal abnormalities and the promotion of neurological illnesses is the ubiquitinated protein TDP-43. Previous studies have shown that mutation in the TARDBP and FUS genes also cause neuronal degeneration and muscular atrophy.
#41 Researching motor neurone disease: highlight notice – UKRI
https://www.ukri.org/opportunity/researching-motor-neurone-disease-highlight-notice/
MND is a devastating neurodegenerative disease, characterised by loss of motor neurone function. In patients suffering with MND, signals from the motor neurones gradually stop reaching the muscles causing them to weaken, stiffen and waste. […] Research on MND is at an exciting juncture. Significant advances in understanding disease pathogenesis and identifying therapeutic targets are attracting unprecedented interest from industry and a genuine optimism that this disease is tractable. […] improve the mechanistic understanding of MND, including identification and validation of new biomarkers […] investigate potential new therapeutic avenues. […] Damage to functions regulated by ER-mitochondria signalling, mediated by VAPB-PTPIP51, is a feature of ALS therefore this work could facilitate the design of potential therapeutics. […] This clinician scientist fellowship investigates changes in metabolism in two mouse models of MND in order to identify common changes that could be used as therapeutic targets.
#42 Tomorrow Bio 4.0
https://www.tomorrow.bio/post/uq-researchers-have-mapped-out-the-proteins-implicated-in-the-early-stages-of-motor-neurone-disease-mnd-2024-02-6114846356-neuroscience
The study found that DNAJB5 levels significantly increased before the onset of MND, particularly in areas of the brain where another protein called TDP-43 aggregates. This suggests that the elevation of DNAJB5 may represent a protective mechanism by neurons to control TDP-43 dysfunction. […] Understanding the intricate details of protein interactions within the context of MND offers a glimpse into the complex mechanisms underlying this neurodegenerative disease. […] The identification of specific proteins and biomarkers associated with MND not only sheds light on the pathophysiology of the condition but also provides potential targets for therapeutic interventions. […] The identification of potential biomarkers for the early detection of MND is a significant breakthrough. […] By understanding the proteins involved in the early stages of the disease, researchers can develop targeted therapies that aim to restore or protect motor neurons, potentially halting or reversing the progression of MND.
#43 Tomorrow Bio 4.0
https://www.tomorrow.bio/post/uq-researchers-have-mapped-out-the-proteins-implicated-in-the-early-stages-of-motor-neurone-disease-mnd-2024-02-6114846356-neuroscience
The study found that DNAJB5 levels significantly increased before the onset of MND, particularly in areas of the brain where another protein called TDP-43 aggregates. This suggests that the elevation of DNAJB5 may represent a protective mechanism by neurons to control TDP-43 dysfunction. […] Understanding the intricate details of protein interactions within the context of MND offers a glimpse into the complex mechanisms underlying this neurodegenerative disease. […] The identification of specific proteins and biomarkers associated with MND not only sheds light on the pathophysiology of the condition but also provides potential targets for therapeutic interventions. […] The identification of potential biomarkers for the early detection of MND is a significant breakthrough. […] By understanding the proteins involved in the early stages of the disease, researchers can develop targeted therapies that aim to restore or protect motor neurons, potentially halting or reversing the progression of MND.
#44 Researching motor neurone disease: highlight notice – UKRI
https://www.ukri.org/opportunity/researching-motor-neurone-disease-highlight-notice/
MND is a devastating neurodegenerative disease, characterised by loss of motor neurone function. In patients suffering with MND, signals from the motor neurones gradually stop reaching the muscles causing them to weaken, stiffen and waste. […] Research on MND is at an exciting juncture. Significant advances in understanding disease pathogenesis and identifying therapeutic targets are attracting unprecedented interest from industry and a genuine optimism that this disease is tractable. […] improve the mechanistic understanding of MND, including identification and validation of new biomarkers […] investigate potential new therapeutic avenues. […] Damage to functions regulated by ER-mitochondria signalling, mediated by VAPB-PTPIP51, is a feature of ALS therefore this work could facilitate the design of potential therapeutics. […] This clinician scientist fellowship investigates changes in metabolism in two mouse models of MND in order to identify common changes that could be used as therapeutic targets.
#45 Blog â The Quest to Understand Motor Neuron DiseaseFeatured
https://www.dementiaresearcher.nihr.ac.uk/blog-the-quest-to-understand-motor-neuron-disease/
I hope that we can find the molecular mechanism behind synapse loss and identify new targets for further drug discovery and therapeutic treatment, which could prove to be life changing for people living with the disease. […] Interestingly nearly half of the people living with MND shows some form of change in cognitive skills as well as problems with movement. The toxic effect of glia cells has already been showed in other diseases and some interesting pathways have been already targeted. We would like to know if the same approach can be applied to MND and if this could lead to the development of new drugs to treat it. […] One very exciting development on the field is the positive outcome of personalized gene therapy. This type of treatment is in the later stages of the clinical trial process. Personalized gene therapy means that researchers can engineer specific molecules to silent a target gene, in the most recent example, the FUS gene. […] I aim to examine how glia cells react to MND affected synapses, how we can target glia to decrease the ingestion of synapses and ultimately prevent neuronal loss.
#46 Motor Neurone Disease Breakthroughs | Open Medscience
https://openmedscience.com/motor-neurone-disease-diagnosis-and-future-research-insights/
Neuroinflammation is increasingly recognised as a contributing factor in MND pathogenesis. Microglia, the brainâs resident immune cells, become activated in MND and may contribute to motor neurone damage. Targeting neuroinflammation with immunomodulatory drugs or therapies that modulate microglial activity is an area of active research. Understanding the role of the immune system in MND could lead to novel treatments that slow or stop disease progression. […] Abnormal protein aggregation is a hallmark of MND, particularly in ALS, where proteins such as TDP-43 form toxic aggregates within motor neurones. Research is focused on understanding the mechanisms of protein aggregation and misfolding, as well as developing therapeutic strategies to prevent or clear these aggregates. Several approaches are being explored, including small molecules that enhance protein degradation pathways, such as the ubiquitin-proteasome system or autophagy, and immunotherapy targeting misfolded proteins. The goal is to reduce the toxic burden on motor neurones and slow the progression of the disease.
#47 Motor Neurone Disease Breakthroughs | Open Medscience
https://openmedscience.com/motor-neurone-disease-diagnosis-and-future-research-insights/
Neuroinflammation is increasingly recognised as a contributing factor in MND pathogenesis. Microglia, the brainâs resident immune cells, become activated in MND and may contribute to motor neurone damage. Targeting neuroinflammation with immunomodulatory drugs or therapies that modulate microglial activity is an area of active research. Understanding the role of the immune system in MND could lead to novel treatments that slow or stop disease progression. […] Abnormal protein aggregation is a hallmark of MND, particularly in ALS, where proteins such as TDP-43 form toxic aggregates within motor neurones. Research is focused on understanding the mechanisms of protein aggregation and misfolding, as well as developing therapeutic strategies to prevent or clear these aggregates. Several approaches are being explored, including small molecules that enhance protein degradation pathways, such as the ubiquitin-proteasome system or autophagy, and immunotherapy targeting misfolded proteins. The goal is to reduce the toxic burden on motor neurones and slow the progression of the disease.
#48 The Role of Stress in the Progression of Motor Neuron Disease: Mechanisms and Implications for Treatment
https://www.sciopen.com/article/10.26599/SAB.2023.9060002
Motor neuron diseases (MND) are a group of rare neurodegenerative diseases that significantly affect the survival of patients. […] This review also discusses the potential mechanisms of stress-induced MND deterioration, including activation of the hypothalamic-pituitary-adrenal axis, abnormal microglial activation, oxidative stress, and the accumulation of stress granules. […] The role of stress in the pathological changes of MND and the importance of stress management in the treatment of MND have been emphasized.
#49 The Role of Stress in the Progression of Motor Neuron Disease: Mechanisms and Implications for Treatment
https://www.sciopen.com/article/10.26599/SAB.2023.9060002
Motor neuron diseases (MND) are a group of rare neurodegenerative diseases that significantly affect the survival of patients. […] This review also discusses the potential mechanisms of stress-induced MND deterioration, including activation of the hypothalamic-pituitary-adrenal axis, abnormal microglial activation, oxidative stress, and the accumulation of stress granules. […] The role of stress in the pathological changes of MND and the importance of stress management in the treatment of MND have been emphasized.
#50 Motor Neurone Disease Group | Research Group | The Florey
https://florey.edu.au/research-group/motor-neurone-disease-group/
Neurodegenerative diseases have a devastating impact on quality of life and impose a tremendous burden on the health care system. Motor neurone disease (MND) is the most rapidly fatal, with increasing physical disability and death typically within 2-3 years from the onset of symptoms. […] Our group uses a combination of cell and molecular biology to unravel MND pathogenesis in patient-derived biosamples, cell culture systems and animal models. We seek to identify and understand the primary mechanisms underlying motor neuron vulnerability and degeneration in MND, while translating our discoveries into relevant targets for effective intervention. […] Key research questions weâre investigating include: What is the fundamental cause of ALS? When does motor neuron vulnerability start in ALS? Where does ALS originate in the central nervous system? What is the primary cell death pathway(s) mediating motor neuron loss in ALS? How early do we need to intervene with treatments in ALS? Do ALS, SMA and KD share a common pathogenesis? […] Mapping the origin and onset of MND â transcriptomic profiling of motor neuron populations in MND. […] Using DREADDs to deconstruct motor neuron disease.
#51 Motor Neurone Disease Group | Research Group | The Florey
https://florey.edu.au/research-group/motor-neurone-disease-group/
Neurodegenerative diseases have a devastating impact on quality of life and impose a tremendous burden on the health care system. Motor neurone disease (MND) is the most rapidly fatal, with increasing physical disability and death typically within 2-3 years from the onset of symptoms. […] Our group uses a combination of cell and molecular biology to unravel MND pathogenesis in patient-derived biosamples, cell culture systems and animal models. We seek to identify and understand the primary mechanisms underlying motor neuron vulnerability and degeneration in MND, while translating our discoveries into relevant targets for effective intervention. […] Key research questions weâre investigating include: What is the fundamental cause of ALS? When does motor neuron vulnerability start in ALS? Where does ALS originate in the central nervous system? What is the primary cell death pathway(s) mediating motor neuron loss in ALS? How early do we need to intervene with treatments in ALS? Do ALS, SMA and KD share a common pathogenesis? […] Mapping the origin and onset of MND â transcriptomic profiling of motor neuron populations in MND. […] Using DREADDs to deconstruct motor neuron disease.
#52 Motor Neurone Disease Group | Research Group | The Florey
https://florey.edu.au/research-group/motor-neurone-disease-group/
Neurodegenerative diseases have a devastating impact on quality of life and impose a tremendous burden on the health care system. Motor neurone disease (MND) is the most rapidly fatal, with increasing physical disability and death typically within 2-3 years from the onset of symptoms. […] Our group uses a combination of cell and molecular biology to unravel MND pathogenesis in patient-derived biosamples, cell culture systems and animal models. We seek to identify and understand the primary mechanisms underlying motor neuron vulnerability and degeneration in MND, while translating our discoveries into relevant targets for effective intervention. […] Key research questions weâre investigating include: What is the fundamental cause of ALS? When does motor neuron vulnerability start in ALS? Where does ALS originate in the central nervous system? What is the primary cell death pathway(s) mediating motor neuron loss in ALS? How early do we need to intervene with treatments in ALS? Do ALS, SMA and KD share a common pathogenesis? […] Mapping the origin and onset of MND â transcriptomic profiling of motor neuron populations in MND. […] Using DREADDs to deconstruct motor neuron disease.
#53 Tomorrow Bio 4.0
https://www.tomorrow.bio/post/uq-researchers-have-mapped-out-the-proteins-implicated-in-the-early-stages-of-motor-neurone-disease-mnd-2024-02-6114846356-neuroscience
The study found that DNAJB5 levels significantly increased before the onset of MND, particularly in areas of the brain where another protein called TDP-43 aggregates. This suggests that the elevation of DNAJB5 may represent a protective mechanism by neurons to control TDP-43 dysfunction. […] Understanding the intricate details of protein interactions within the context of MND offers a glimpse into the complex mechanisms underlying this neurodegenerative disease. […] The identification of specific proteins and biomarkers associated with MND not only sheds light on the pathophysiology of the condition but also provides potential targets for therapeutic interventions. […] The identification of potential biomarkers for the early detection of MND is a significant breakthrough. […] By understanding the proteins involved in the early stages of the disease, researchers can develop targeted therapies that aim to restore or protect motor neurons, potentially halting or reversing the progression of MND.
#54 Tomorrow Bio 4.0
https://www.tomorrow.bio/post/uq-researchers-have-mapped-out-the-proteins-implicated-in-the-early-stages-of-motor-neurone-disease-mnd-2024-02-6114846356-neuroscience
The study found that DNAJB5 levels significantly increased before the onset of MND, particularly in areas of the brain where another protein called TDP-43 aggregates. This suggests that the elevation of DNAJB5 may represent a protective mechanism by neurons to control TDP-43 dysfunction. […] Understanding the intricate details of protein interactions within the context of MND offers a glimpse into the complex mechanisms underlying this neurodegenerative disease. […] The identification of specific proteins and biomarkers associated with MND not only sheds light on the pathophysiology of the condition but also provides potential targets for therapeutic interventions. […] The identification of potential biomarkers for the early detection of MND is a significant breakthrough. […] By understanding the proteins involved in the early stages of the disease, researchers can develop targeted therapies that aim to restore or protect motor neurons, potentially halting or reversing the progression of MND.
#55 Tomorrow Bio 4.0
https://www.tomorrow.bio/post/uq-researchers-have-mapped-out-the-proteins-implicated-in-the-early-stages-of-motor-neurone-disease-mnd-2024-02-6114846356-neuroscience
Proteins play a crucial role in the development and progression of Motor Neuron Disease (MND), also known as Amyotrophic Lateral Sclerosis (ALS). […] By mapping the proteins involved in MND, researchers can gain valuable insights into the disease and potentially develop new therapeutic strategies. […] The UQ research team conducted an extensive study to map out the proteins implicated in the early stages of MND. […] One such protein is DNAJB5, which is a chaperone protein involved in the protein folding process. […] This elevation of DNAJB5 suggests a potential role in the early stages of MND pathogenesis, possibly as a protective response by neurons to control the dysfunction of another protein called TDP-43. […] Understanding the roles of proteins like DNAJB5 in the early stages of MND is essential for identifying potential therapeutic targets and developing strategies for disease intervention and treatment.
#56 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.
#57 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.