Annals of Clinical and Experimental NeurologyAnnals of Clinical and Experimental NeurologyАнналы клинической и экспериментальной неврологии2075-54732409-2533Eco-Vector107010.17816/ACEN.1070ReviewsОбзорыReview ArticleMechanisms of neuromuscular junction dysfunction in amyotrophic lateral sclerosisМеханизмы развития дисфункции нервно-мышечных синапсов при боковом амиотрофическом склерозеhttps://orcid.org/0000-0001-5625-8658KhabibrakhmanovAydar N.ХабибрахмановАйдар Назимович
Russian Federation

junior researcher, Institute of Neurosciences

м. н. с. Института нейронаук

marat.muhamedyarov@kazangmu.ruhttps://orcid.org/0009-0000-4926-3192AkhmadievaLiaisan A.АхмадиеваЛяйсан Айдаровна
Russian Federation

junior researcher

м. н. с. Института нейронаук

marat.muhamedyarov@kazangmu.ruhttps://orcid.org/0009-0000-1577-9780NagievKerim K.НагиевКерим Казбекович
Russian Federation

lecturer, Department of the normal physiology

ассистент каф. нормальной физиологии

marat.muhamedyarov@kazangmu.ruhttps://orcid.org/0000-0002-0397-9002MukhamedyarovMarat A.МухамедьяровМарат Александрович
Russian Federation

Dr. Sci. (Med.), Professor, Head, Department of the normal physiology; Director, Institute of Neurosciences

д-р мед. наук, профессор, зав. каф. нормальной физиологии, директор Института нейронаук

marat.muhamedyarov@kazangmu.ruKazan State Medical UniversityКазанский государственный медицинский университет1503202519153610712202311122023Copyright ©; 2025, Khabibrakhmanov A.N., Akhmadieva L.A., Nagiev K.K., Mukhamedyarov M.A.Copyright ©; 2025, Хабибрахманов А.Н., Ахмадиева Л.А., Нагиев К.К., Мухамедьяров М.А.2025Khabibrakhmanov A.N., Akhmadieva L.A., Nagiev K.K., Mukhamedyarov M.A.Хабибрахманов А.Н., Ахмадиева Л.А., Нагиев К.К., Мухамедьяров М.А.https://creativecommons.org/licenses/by/4.0https://annaly-nevrologii.com/pathID/article/view/1070

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the death of upper and lower motor neurons. Numerous studies show that structural and functional impairments of neuromuscular junctions (NMJ) occur as early as the presymptomatic stage of ALS. NMJ involvement is independent and one of the primary events in ALS pathogenesis. Aim: to review the data on characteristics and mechanisms of NMJ dysfunction at pre- and postsynaptic levels in ALS patients and a transgenic animal model of the disease. Furthermore, we report on the dysfunction of perisynaptic Schwann cells and impaired mechanisms of motor neuron and skeletal muscle interaction in ALS, with a focus on reviewed publications on targeting of molecular mechanisms underlying NMJ dysfunction and disruption in ALS. The NMJ may be a potential target for novel therapeutic approaches for ALS.

Боковой амиотрофический склероз (БАС) является прогрессирующим нейродегенеративным заболеванием, характеризующимся гибелью верхних и нижних мотонейронов. В многочисленных исследованиях показано, что структурно-функциональные нарушения нервно-мышечных синапсов (НМС) при БАС развиваются уже на досимптомной стадии болезни. Поражение НМС является самостоятельным и одним из первичных патогенетических процессов при БАС. Цель обзора — анализ научных данных о характере поражения и механизмах нарушения функционирования НМС на пре- и постсинаптическом уровне при БАС у пациентов и в модели данного заболевания на трансгенных животных. Кроме того, представлены сведения о дисфункции перисинаптических шванновских клеток и о нарушении механизмов взаимодействия мотонейрона и скелетной мышцы при БАС. Особое внимание уделено анализу научных работ, связанных с коррекцией молекулярных механизмов, лежащих в основе дисфункции и деструкции НМС при БАС. Сделан вывод о том, что НМС может выступать потенциальной мишенью для разработки новых терапевтических подходов при БАС.

amyotrophic lateral sclerosisneuromuscular junctionnerve terminalskeletal musclemotor unitбоковой амиотрофический склерознервно-мышечный синапснервное окончаниескелетная мышцадвигательная единицаRussian Science FoundationРоссийский научный фонд23-15-00438Hardiman O, Al-Chalabi A, Chio A, et al. Amyotrophic lateral sclerosis. Nat Rev Dis Primers. 2017;3:17071. DOI: 10.1038/nrdp.2017.71Хондкариан О.А., Бунина Т.Л., Завалишин И.А. Боковой амиотрофический склероз. М.; 1978. 264 c. Khondkarian OA, Bunina TL, Zavalishin IA. Amyotrophic lateral sclerosis. Moscow; 1978. 264 p. (In Russ.)Körner S, Kollewe K, Fahlbusch M, et al. Onset and spreading patterns of upper and lower motor neuron symptoms in amyotrophic lateral sclerosis. Muscle Nerve. 2011;43(5):636–642. DOI: 10.1002/mus.21936Traxinger K, Kelly C, Johnson BA, et al. Prognosis and epidemiology of amyotrophic lateral sclerosis: analysis of a clinic population, 1997–2011. Neurol Clin Pract. 2013;3(4):313–320. DOI: 10.1212/CPJ.0b013e3182a1b8abGrad LI, Rouleau GA, Ravits J, Cashman NR. Clinical spectrum of amyotrophic lateral sclerosis (ALS). Cold Spring Harb Perspect Med. 2017;7(8):a024117. DOI: 10.1101/cshperspect.a024117Мухамедьяров М.А., Хабибрахманов А.Н., Зефиров А.Л. Ранние дисфункции при боковом амиотрофическом склерозе: патогенетические механизмы и роль в инициации заболевания. Биологические мембраны: журнал мембранной и клеточной биологии. 2020;37(4):264–270. Mukhamedyarov MA, Khabibrakhmanov AN, Zefirov AL. Early dysfunctions in amyotrophic lateral sclerosis: pathogenetic mechanisms and a role in disease initiation of the disease. Biochemistry (Moscow), Supplement Series A: Membrane and Cell Biology. 2020;14(4):261–266. DOI: 10.1134/S1990747820030113Masrori P, Van Damme P. Amyotrophic lateral sclerosis: a clinical review. Eur J Neurol. 2020;27(10):1918–1929. DOI: 10.1111/ene.14393Brown RH, Al-Chalabi A. Amyotrophic lateral sclerosis. N Engl J Med. 2017;377(2):162–172. DOI: 10.1056/NEJMra1603471Мухамедьяров М.А., Петров А.М., Григорьев П.Н. и др. Боковой амиотрофический склероз: современные представления о патогенезе и экспериментальные модели. Журнал высшей нервной деятельности им И.П. Павлова. 2018;68(5):551–566. Mukhamedyarov MA, Petrov AM, Grigoriyev PN et al. Amyotrophic lateral sclerosis: current understanding of the pathogenesis and experimental model. Zh Vyssh Nerv Deiat IP Pavlova. 2018;68(5):551–566. DOI: 10.1134/S0044467718050106Rothstein JD, Tsai G, Kuncl RW, et al. Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis. Ann Neurol. 1990;28(1):18–25. DOI: 10.1002/ana.410280106Verma S, Khurana S, Vats A, et al. Neuromuscular junction dysfunction in amyotrophic lateral sclerosis. Mol Neurobiol. 2022;59(3):1502–1527. DOI: 10.1007/s12035-021-02658-6Eisen A., Nakajima M., Weber M. Corticomotorneuronal hyper-excitability in amyotrophic lateral sclerosis. J Neurol Sci 1998;160(Suppl 1):S64–68. DOI: 10.1016/S0022-510X(98)00200-7Kiernan MC, Vucic S, Cheah BC, et al. Amyotrophic lateral sclerosis. Lancet. 2011;377(9769):942–955. DOI: 10.1016/S0140-6736(10)61156-7Dadon-Nachum M, Melamed E, Offen D. The “dying-back” phenomenon of motor neurons in ALS. J. Mol. Neurosci. 2011;43(3):470–477. DOI: 10.1007/s12031-010-9467-1Pamphlett R, Kril J, Hng TM. Motor neuron disease: a primary disorder of corticomotoneurons? Muscle Nerve. 1995;18(3):314–318. DOI: 10.1002/mus.880180308Attarian S, Vedel J, Pouget J, Schmied A. Progression of cortical and spinal dysfunctions over time in amyotrophic lateral sclerosis. Muscle Nerve. 2008;37(3):364–375. DOI: 10.1002/mus.20942Mukhamedyarov MA, Khabibrakhmanov AN, Khuzakhmetova VF, et al. Early alterations in structural and functional properties in the neuromuscular junctions of mutant FUS mice. Int J Mol Sci. 2023;24(10):9022. DOI: 10.3390/ijms24109022Verma S, Khurana S, Gourie-Devi M, et al. Multiomics approach reveal novel insights in FUS driven juvenile amyotrophic lateral sclerosis: a family quartet analysis. Ann Neurosci. 2023. DOI: 10.1177/09727531231194399Hennig R, Lømo T. Firing patterns of motor units in normal rats. Nature. 1985;314(6007):164–166. DOI: 10.1038/314164a0Burke RE, Levine DN, Zajac FE, et al. Mammalian motor units: physiological-histochemical correlation in three types in cat gastrocnemius. Science. 1971;174(4010):709–712. DOI: 10.1126/science.174.4010.709Burke RE, Dum RP, Fleshman JW, et al. An HRP study of the relation between cell size and motor unit type in cat ankle extensor motoneurons. J Comp Neurol. 1982;209(1):17–28. DOI: 10.1002/cne.902090103Cullheim S, Fleshman JW, Glenn LL, Burke RE. Membrane area and dendritic structure in type‐identified triceps surae alpha motoneurons. J Comp Neurol. 1987;255(1):68–81. DOI: 10.1002/cne.902550106Kernell D, Zwaagstra B. Input conductance, axonal conduction velocity and cell size among hindlimb motoneurones of the cat. Brain Res. 1981;204(2):311–326. DOI: 10.1016/0006-8993(81)90591-6Mendell LM. The size principle: a rule describing the recruitment of motoneurons. J Neurophysiol. 2005;93(6):3024–3026. DOI: 10.1152/classicessays.00025.2005Tremblay E, Martineau É, Robitaille R. Opposite synaptic alterations at the neuromuscular junction in an ALS mouse model: when motor units matter. J Neurosci. 2017;37(37):8901–8918. DOI: 10.1523/JNEUROSCI.3090-16.2017Pun S, Santos AF, Saxena S, et al. Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF. Nat Neurosci. 2006;9(3):408–419. DOI: 10.1038/nn1653Bjornskov EK, Norris FH, Mower-Kuby J. Quantitative axon terminal and end-plate morphology in amyotrophic lateral sclerosis. Arch Neurol. 1984;41(5):527–530. DOI: 10.1001/archneur.1984.04050170073021Tsujihata M, Hazama R, Yoshimura T, et al. The motor end‐plate fine structure and ultrastructural localization of acetylcholine receptors in amyotrophic lateral sclerosis. Muscle Nerve. 1984;7(3):243–249. DOI: 10.1002/mus.880070310Palma E, Reyes-Ruiz JM, Lopergolo D, et al. Acetylcholine receptors from human muscle as pharmacological targets for ALS therapy. Proc Natl Acad Sci U S A. 2016;113(11):3060–3065. DOI: 10.1073/pnas.1600251113Ding Q, Kesavan K, Lee KM, et al. Impaired signaling for neuromuscular synaptic maintenance is a feature of motor neuron disease. Acta Neuropathol Commun. 2022;10(1):61. DOI: 10.1186/s40478-022-01360-5Dengler R, Konstanzer A, Küther G, et al. Amyotrophic lateral sclerosis: Macro–EMG and twitch forces of single motor units. Muscle Nerve. 1990;13(6):545–550. DOI: 10.1002/mus.880130612Nijssen J, Comley LH, Hedlund E. Motor neuron vulnerability and resistance in amyotrophic lateral sclerosis. Acta Neuropathol. 2017;133(6):863–885. DOI: 10.1007/s00401-017-1708-8Fischer LR, Culver DG, Tennant P, et al. Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp Neurol. 2004;185(2):232–240. DOI: 10.1016/j.expneurol.2003.10.004Maselli RA, Wollman RL, Leung C, et al. Neuromuscular transmission in amyotrophic lateral sclerosis. Muscle Nerve. 1993;16(11):1193–1203. DOI: 10.1002/mus.880161109Bonifacino T, Zerbo RA, Balbi M, et al. Nearly 30 years of animal models to study amyotrophic lateral sclerosis: a historical overview and future perspectives. Int J Mol Sci. 2021;22(22):12236. DOI: 10.3390/ijms222212236Rosen DR, Siddique T, Patterson D, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993;362(6415):59–62. DOI: 10.1038/362059a0Gurney ME, Pu H, Chiu AY, et al. Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science. 1994;264(5166):1772–1775. DOI: 10.1126/science.8209258Bosco DA, Morfini G, Karabacak NM, et al. Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS. Nat Neurosci. 2010;13(11):1396–1403. DOI: 10.1038/nn.2660Huang C, Zhou H, Tong J, et al. FUS transgenic rats develop the phenotypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. PLoS Genet. 2011;7(3):e1002011. DOI: 10.1371/journal.pgen.1002011Verbeeck C, Deng Q, DeJesus-Hernandez M, et al. Expression of Fused in sarcoma mutations in mice recapitulates the neuropathology of FUS proteinopathies and provides insight into disease pathogenesis. Mol Neurodegener. 2012;7:53. DOI: 10.1186/1750-1326-7-53Mitchell JC, McGoldrick P, Vance C, et al. Overexpression of human wild-type FUS causes progressive motor neuron degeneration in an age- and dose-dependent fashion. Acta Neuropathol. 2013;125(2):273–288. DOI: 10.1007/s00401-012-1043-zShelkovnikova TA, Peters OM, Deykin AV, et al. Fused in sarcoma (FUS) protein lacking nuclear localization signal (NLS) and major RNA binding motifs triggers proteinopathy and severe motor phenotype in transgenic mice. J Biol Chem. 2013;288(35):25266–25274. DOI: 10.1074/jbc.M113.492017Yun Y, Ha Y. CRISPR/Cas9-mediated gene correction to understand ALS. Int J Mol Sci. 2020;21(11):3801. DOI: 10.3390/ijms21113801Tsao W, Jeong YH, Lin S, et al. Rodent models of TDP-43: recent advances. Brain Res. 2012;1462:26–39. DOI: 10.1016/j.brainres.2012.04.031Riemslagh FW, van der Toorn EC, Verhagen RFM, et al. Inducible expression of human C9ORF72 36× G4C2 hexanucleotide repeats is sufficient to cause RAN translation and rapid muscular atrophy in mice. Dis Model Mech. 2021;14(2):dmm044842. DOI: 10.1242/dmm.044842Gould TW, Buss RR, Vinsant S, et al. Complete dissociation of motor neuron death from motor dysfunction by Bax deletion in a mouse model of ALS. J Neurosci. 2006;26(34):8774–8786. DOI: 10.1523/JNEUROSCI.2315-06.2006Vinsant S, Mansfield C, Jimenez‐Moreno R, et al. Characterization of early pathogenesis in the SOD1G93A mouse model of ALS: part I, background and methods. Brain Behav. 2013;3(4):335–350. DOI: 10.1002/brb3.143Hegedus J, Putman CT, Tyreman N, Gordon T. Preferential motor unit loss in the SOD1 G93A transgenic mouse model of amyotrophic lateral sclerosis. J Physiol. 2008;586(14):3337–3351. DOI: 10.1113/jphysiol.2007.149286Khabibrakhmanov AN, Nurullin LF, Bogdanov EI, et al. Analysis of immunoexpression of synaptic proteins in neuromuscular junctions of symptomatic and presymptomatic mSOD1 transgenic mice with model of amyotrophic lateral sclerosis. BioNanoScience. 2020;10:375–380. DOI: 10.1007/s12668-019-00711-2Giniatullin A, Petrov A, Giniatullin R. Action of hydrogen peroxide on synaptic transmission at the mouse neuromuscular junction. Neuroscience. 2019;399:135–145. DOI: 10.1016/j.neuroscience.2018.12.027Smith EF, Shaw PJ, De Vos KJ. The role of mitochondria in amyotrophic lateral sclerosis. Neurosci Lett. 2019;710:132933. DOI: 10.1016/j.neulet.2017.06.052Mukhamedyarov MA, Grigoryev PN, Khisamieva GA, et al. Dysfunction of neuromuscular synaptic transmission and synaptic vesicle recycling in motor nerve terminals of mSOD1 transgenic mice with model of amyotrophic lateral sclerosis. BioNanoScience. 2019;9:66–73. DOI: 10.1007/s12668-018-0590-8So E, Mitchell JC, Memmi C, et al. Mitochondrial abnormalities and disruption of the neuromuscular junction precede the clinical phenotype and motor neuron loss in hFUSWT transgenic mice. Hum Mol Genet. 2018;27(3):463–474. DOI: 10.1093/hmg/ddx415Picchiarelli G, Demestre M, Zuko A, et al. FUS-mediated regulation of acetylcholine receptor transcription at neuromuscular junctions is compromised in amyotrophic lateral sclerosis. Nat Neurosci. 2019;22(11):1793–1805. DOI: 10.1038/s41593-019-0498-9Sharma A, Lyashchenko AK, Lu L, et al. ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function. Nat Commun. 2016;7:10465. DOI: 10.1038/ncomms10465Sahadevan S, Hembach KM, Tantardini E, et al. Synaptic FUS accumulation triggers early misregulation of synaptic RNAs in a mouse model of ALS. Nat Commun. 2021;12(1):3027. DOI: 10.1038/s41467-021-23188-8Salam S, Tacconelli S, Smith BN et al. Identification of a novel interaction of FUS and syntaphilin may explain synaptic and mitochondrial abnormalities caused by ALS mutations. Sci Rep. 2021;11(1):13613. DOI: 10.1038/s41598-021-93189-6Chand KK, Lee KM, Lee JD, et al. Defects in synaptic transmission at the neuromuscular junction precede motor deficits in a TDP‐43 Q331K transgenic mouse model of amyotrophic lateral sclerosis. FASEB J. 2018;32(5):2676–2689. DOI: 10.1096/fj.201700835RClark JA, Southam KA, Blizzard CA, et al. Axonal degeneration, distal collateral branching and neuromuscular junction architecture alterations occur prior to symptom onset in the SOD1G93A mouse model of amyotrophic lateral sclerosis. J Chem Neuroanat. 2016;76(Pt A):35–47. DOI: 10.1016/j.jchemneu.2016.03.003Turner BJ, Lopes EC, Cheema SS. Neuromuscular accumulation of mutant superoxide dismutase 1 aggregates in a transgenic mouse model of familial amyotrophic lateral sclerosis. Neurosci Lett. 2003;350(2):132–136. DOI: 10.1016/S0304-3940(03)00893-0Dewil M, dela Cruz VF, Van Den Bosch L, Robberecht W. Inhibition of p38 mitogen activated protein kinase activation and mutant SOD1G93A-induced motor neuron death. Neurobiol Dis. 2007;26(2):332–341. DOI: 10.1016/j.nbd.2006.12.023Wong M, Martin LJ. Skeletal muscle-restricted expression of human SOD1 causes motor neuron degeneration in transgenic mice. Hum Mol Genet. 2010;19(11):2284–2302. DOI: 10.1093/hmg/ddq106Anakor E, Milla V, Connolly O, et al. The neurotoxicity of vesicles secreted by ALS patient myotubes is specific to exosome-like and not larger subtypes. Cells. 2022;11(5):845. DOI: 10.3390/cells11050845Le Gall L, Duddy WJ, Martinat C, et al. Muscle cells of sporadic amyotrophic lateral sclerosis patients secrete neurotoxic vesicles. J Cachexia Sarcopenia Muscle. 2022;13(2):1385–1402. DOI: 10.1002/jcsm.12945Jokic N, Gonzalez de Aguilar J, Dimou L, et al. The neurite outgrowth inhibitor Nogo‐A promotes denervation in an amyotrophic lateral sclerosis model. EMBO Rep. 2006;7(11):1162–1167. DOI: 10.1038/sj.embor.7400826Bruneteau G, Bauché S, Gonzalez de Aguilar JL, et al. Endplate denervation correlates with Nogo-A muscle expression in amyotrophic lateral sclerosis patients. Ann Clin Transl Neurol. 2015;2(4):362–272. DOI: 10.1002/acn3.179Bros-Facer V, Krull D, Taylor A, et al. Treatment with an antibody directed against Nogo-A delays disease progression in the SOD1G93A mouse model of amyotrophic lateral sclerosis. Hum Mol Genet. 2014;23(16):4187–4200. DOI: 10.1093/hmg/ddu136Dupuis L, Loeffler JP. Neuromuscular junction destruction during amyotrophic lateral sclerosis: insights from transgenic models. Curr Opin Pharmacol. 2009;9(3):341–346. DOI: 10.1016/j.coph.2009.03.007Dupuis L, Oudart H, René F, et al. Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: benefit of a high-energy diet in a transgenic mouse model. Proc Natl Acad Sci U S A. 2004;101(30):11159–11164. DOI: 10.1073/pnas.0402026101Martineau É, Arbour D, Vallée J, Robitaille R. Properties of glial cell at the neuromuscular junction are incompatible with synaptic repair in the SOD1 G37R ALS mouse model. J Neurosci. 2020;40(40):7759–7777. DOI: 10.1523/JNEUROSCI.1748-18.2020Harrison JM, Rafuse VF. Muscle fiber-type specific terminal Schwann cell pathology leads to sprouting deficits following partial denervation in SOD1G93A mice. Neurobiol Dis. 2020;145:105052. DOI: 10.1016/j.nbd.2020.105052Alhindi A, Shand M, Smith HL, et al. Neuromuscular junction denervation and terminal Schwann cell loss in the hTDP‐43 overexpression mouse model of amyotrophic lateral sclerosis. Neuropathol Appl Neurobiol. 2023;49(4):e12925. DOI: 10.1111/nan.12925Winter F De, Vo T, Stam FJ, et al. The expression of the chemorepellent Semaphorin 3A is selectively induced in terminal Schwann cells of a subset of neuromuscular synapses that display limited anatomical plasticity and enhanced vulnerability in motor neuron disease. Mol Cell Neurosci. 2006;32(1-2):102–117. DOI: 10.1016/j.mcn.2006.03.002Maimon R, Ionescu A, Bonnie A, et al. miR126-5p downregulation facilitates axon degeneration and NMJ disruption via a non-cell-autonomous mechanism in ALS. J Neurosci. 2018;38(24):5478–5494. DOI: 10.1523/JNEUROSCI.3037-17.2018Mora JS, Genge A, Chio A, et al. Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomized clinical trial. Amyotroph Lateral Scler Frontotemporal Degener. 2020;21(1-2):5–14. DOI: 10.1080/21678421.2019.1632346Saini J, Faroni A, Reid AJ, et al. Cross‐talk between motor neurons and myotubes via endogenously secreted neural and muscular growth factors. Physiol Rep. 2021;9(8):e14791. DOI: 10.14814/phy2.14791Ma G, Wang Y, Li Y, et al. MiR-206, a key modulator of skeletal muscle development and disease. Int J Biol Sci. 2015;11(3):345–352. DOI: 10.7150/ijbs.10921Dobrowolny G, Martone J, Lepore E, et al. A longitudinal study defined circulating microRNAs as reliable biomarkers for disease prognosis and progression in ALS human patients. Cell Death Discov. 2021;7(1):4. DOI: 10.1038/s41420-020-00397-6Nishimune H, Shigemoto K. Practical anatomy of the neuromuscular junction in health and disease. Neurol. Clin. 2018;36(2):231–240. DOI: 10.1016/j.ncl.2018.01.009Zong Y, Jin R. Structural mechanisms of the agrin–LRP4–MuSK signaling pathway in neuromuscular junction differentiation. Cell Mol Life Sci. 2013;70(17):3077–3088. DOI: 10.1007/s00018-012-1209-9Tu WY, Xu W, Zhang J, et al. C9orf72 poly-GA proteins impair neuromuscular transmission. Zool Res. 2023;44(2):331–340. DOI: 10.24272/j.issn.2095-8137.2022.356Vilmont V, Cadot B, Vezin E, et al. Dynein disruption perturbs post-synaptic components and contributes to impaired MuSK clustering at the NMJ: implication in ALS. Sci Rep. 2016;6:27804. DOI: 10.1038/srep27804White MA, Kim E, Duffy A, et al. TDP-43 gains function due to perturbed autoregulation in a Tardbp knock-in mouse model of ALS-FTD. Nat Neurosci. 2018;21(4):552–563. DOI: 10.1038/s41593-018-0113-5Cantor S, Zhang W, Delestrée N, et al. Preserving neuromuscular synapses in ALS by stimulating MuSK with a therapeutic agonist antibody. Elife. 2018;7:e34375. DOI: 10.7554/eLife.34375Pérez-García MJ, Burden SJ. Increasing MuSK activity delays denervation and improves motor function in ALS mice. Cell Rep. 2012;2(3):497–502. DOI: 10.1016/j.celrep.2012.08.004Sengupta-Ghosh A, Dominguez SL, Xie L, et al. Muscle specific kinase (MuSK) activation preserves neuromuscular junctions in the diaphragm but is not sufficient to provide a functional benefit in the SOD1G93A mouse model of ALS. Neurobiol Dis. 2019;124:340–352. DOI: 10.1016/j.nbd.2018.12.002Miyoshi S, Tezuka T, Arimura S, et al. DOK7 gene therapy enhances motor activity and life span in ALS model mice. EMBO Mol Med. 2017;9(7):880–889. DOI: 10.15252/emmm.201607298