Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition characterised by a progressive loss of motor neurons controlling voluntary muscle activity. The disease manifests through a variety of motor dysfunctions related to the extent of damage and loss of neurons at different anatomical locations. Despite extensive research, it remains unclear why some motor neurons are especially susceptible to the disease, while others are affected less or even spared. In this article, we review the neurobiological mechanisms, neurochemical profiles, and morpho-functional characteristics of various motor neuron groups and types of motor units implicated in their differential exposure to degeneration. We discuss specific cell-autonomous (intrinsic) and extrinsic factors influencing the vulnerability gradient of motor units and motor neuron types to ALS, with their impact on disease manifestation, course, and prognosis, as revealed in preclinical and clinical studies. We consider the outstanding challenges and emerging opportunities for interpreting the phenotypic and mechanistic variability of the disease to identify targets for clinical interventions.

Center of Biomedical Network Research on Mental Health ISCIII Madrid Spain

Department of Medical Genetics 3rd Faculty of Medicine Charles University Ruská 87 10000 Prague Czech Republic

Faculty of Engineering and Science University of Greenwich London Chatham Maritime Kent ME4 4TB UK

Instituto de Neurociencias UMH CSIC Avda Ramon y Cajal 03550 San Juan de Alicante Spain

Zobrazit více v PubMed

Alappat JJ. Ethnic variation in the incidence of ALS: a systematic review. Neurology. 2007;69(7):711. doi: 10.1212/01.wnl.0000285431.01005.67. PubMed DOI

Alexianu ME, Ho BK, Mohamed AH, La Bella V, Smith RG, Appel SH. The role of calcium-binding proteins in selective motoneuron vulnerability in amyotrophic lateral sclerosis. Ann Neurol. 1994;36(6):846–858. doi: 10.1002/ana.410360608. PubMed DOI

Amado DA, Davidson BL. Gene therapy for ALS: a review. Mol Ther. 2021;29(12):3345–3358. doi: 10.1016/j.ymthe.2021.04.008. PubMed DOI PMC

Baczyk M, Manuel M, Roselli F, Zytnicki D. Diversity of mammalian motoneurons and motor units. Adv Neurobiol. 2022;28:131–150. doi: 10.1007/978-3-031-07167-6_6. PubMed DOI

Baczyk M, Manuel M, Roselli F, Zytnicki D. From physiological properties to selective vulnerability of motor units in amyotrophic lateral sclerosis. Adv Neurobiol. 2022;28:375–394. doi: 10.1007/978-3-031-07167-6_15. PubMed DOI

Bellingham MC. A review of the neural mechanisms of action and clinical efficiency of riluzole in treating amyotrophic lateral sclerosis: what have we learned in the last decade? CNS Neurosci Ther. 2011;17(1):4–31. doi: 10.1111/j.1755-5949.2009.00116.x. PubMed DOI PMC

Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N Engl J Med. 1994;330(9):585–591. doi: 10.1056/NEJM199403033300901. PubMed DOI

Bernard-Marissal N, Moumen A, Sunyach C, Pellegrino C, Dudley K, Henderson CE, Raoul C, Pettmann B. Reduced calreticulin levels link endoplasmic reticulum stress and Fas-triggered cell death in motoneurons vulnerable to ALS. J Neurosci. 2012;32(14):4901–4912. doi: 10.1523/JNEUROSCI.5431-11.2012. PubMed DOI PMC

Bernard-Marissal N, Sunyach C, Marissal T, Raoul C, Pettmann B. Calreticulin levels determine onset of early muscle denervation by fast motoneurons of ALS model mice. Neurobiol Dis. 2015;73:130–136. doi: 10.1016/j.nbd.2014.09.009. PubMed DOI

Boillee S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, Kassiotis G, Kollias G, Cleveland DW. Onset and progression in inherited ALS determined by motor neurons and microglia. Science. 2006;312(5778):1389–1392. doi: 10.1126/science.1123511. PubMed DOI

Brockington A, Ning K, Heath PR, Wood E, Kirby J, Fusi N, Lawrence N, Wharton SB, Ince PG, Shaw PJ. Unravelling the enigma of selective vulnerability in neurodegeneration: motor neurons resistant to degeneration in ALS show distinct gene expression characteristics and decreased susceptibility to excitotoxicity. Acta Neuropathol. 2013;125(1):95–109. doi: 10.1007/s00401-012-1058-5. PubMed DOI PMC

Burke RE. Revisiting the notion of 'motor unit types'. Prog Brain Res. 1999;123:167–175. doi: 10.1016/S0079-6123(08)62854-X. PubMed DOI

Burke RE, Tsairis P. Anatomy and innervation ratios in motor units of cat gastrocnemius. J Physiol. 1973;234(3):749–765. doi: 10.1113/jphysiol.1973.sp010370. PubMed DOI PMC

Burke RE, Levine DN, Zajac FE., 3rd Mammalian motor units: physiological-histochemical correlation in three types in cat gastrocnemius. Science. 1971;174(4010):709–712. doi: 10.1126/science.174.4010.709. PubMed DOI

Burke RE, Levine DN, Salcman M, Tsairis P. Motor units in cat soleus muscle: physiological, histochemical and morphological characteristics. J Physiol. 1974;238(3):503–514. doi: 10.1113/jphysiol.1974.sp010540. PubMed DOI PMC

Burke RE, Dum RP, Fleshman JW, Glenn LL, Lev-Tov A, O'Donovan MJ, Pinter MJ. A 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.902090103. PubMed DOI

Button DC, Kalmar JM, Gardiner K, Cahill F, Gardiner PF. Spike frequency adaptation of rat hindlimb motoneurons. J Appl Physiol (1985) 2007;102(3):1041–1050. doi: 10.1152/japplphysiol.01148.2006. PubMed DOI

Cain MD, Salimi H, Diamond MS, Klein RS. Mechanisms of pathogen invasion into the central nervous system. Neuron. 2019;103(5):771–783. doi: 10.1016/j.neuron.2019.07.015. PubMed DOI

Caligari M, Godi M, Guglielmetti S, Franchignoni F, Nardone A. Eye tracking communication devices in amyotrophic lateral sclerosis: impact on disability and quality of life. Amyotroph Lateral Scler Frontotemporal Degener. 2013;14(7–8):546–552. doi: 10.3109/21678421.2013.803576. PubMed DOI

Chio A, Logroscino G, Traynor BJ, Collins J, Simeone JC, Goldstein LA, White LA. Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature. Neuroepidemiology. 2013;41(2):118–130. doi: 10.1159/000351153. PubMed DOI PMC

Christoforidou E, Joilin G, Hafezparast M. Potential of activated microglia as a source of dysregulated extracellular microRNAs contributing to neurodegeneration in amyotrophic lateral sclerosis. J Neuroinflamm. 2020;17(1):135. doi: 10.1186/s12974-020-01822-4. PubMed DOI PMC

Collaborators GBDMND. Global, regional, and national burden of motor neuron diseases 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2018;17(12):1083–1097. doi: 10.1016/S1474-4422(18)30404-6. PubMed DOI PMC

Comley L, Allodi I, Nichterwitz S, Nizzardo M, Simone C, Corti S, Hedlund E. Motor neurons with differential vulnerability to degeneration show distinct protein signatures in health and ALS. Neuroscience. 2015;291:216–229. doi: 10.1016/j.neuroscience.2015.02.013. PubMed DOI

Comley LH, Nijssen J, Frost-Nylen J, Hedlund E. Cross-disease comparison of amyotrophic lateral sclerosis and spinal muscular atrophy reveals conservation of selective vulnerability but differential neuromuscular junction pathology. J Comp Neurol. 2016;524(7):1424–1442. doi: 10.1002/cne.23917. PubMed DOI PMC

Cullheim 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.902550106. PubMed DOI

Da Cruz S, Parone PA, Lopes VS, Lillo C, McAlonis-Downes M, Lee SK, Vetto AP, Petrosyan S, Marsala M, Murphy AN, Williams DS, Spiegelman BM, Cleveland DW. Elevated PGC-1alpha activity sustains mitochondrial biogenesis and muscle function without extending survival in a mouse model of inherited ALS. Cell Metab. 2012;15(5):778–786. doi: 10.1016/j.cmet.2012.03.019. PubMed DOI PMC

Dadon-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/s12031-010-9467-1. PubMed DOI

de Boer EMJ, Orie VK, Williams T, Baker MR, De Oliveira HM, Polvikoski T, Silsby M, Menon P, van den Bos M, Halliday GM, van den Berg LH, Van Den Bosch L, van Damme P, Kiernan MC, van Es MA, Vucic S. TDP-43 proteinopathies: a new wave of neurodegenerative diseases. J Neurol Neurosurg Psychiatry. 2020;92(1):86–95. doi: 10.1136/jnnp-2020-322983. PubMed DOI PMC

De Winter F, Vo T, Stam FJ, Wisman LA, Bar PR, Niclou SP, van Muiswinkel FL, Verhaagen J. 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.2006.03.002. PubMed DOI

Dengler R, Konstanzer A, Kuther G, Hesse S, Wolf W, Struppler A. Amyotrophic lateral sclerosis—macro-EMG and twitch forces of single motor units. Muscle Nerve. 1990;13(6):545–550. doi: 10.1002/mus.880130612. PubMed DOI

Filezac de L'Etang A, Maharjan N, Cordeiro Brana M, Ruegsegger C, Rehmann R, Goswami A, Roos A, Troost D, Schneider BL, Weis J, Saxena S. Marinesco-Sjogren syndrome protein SIL1 regulates motor neuron subtype-selective ER stress in ALS. Nat Neurosci. 2015;18(2):227–238. doi: 10.1038/nn.3903. PubMed DOI

Fitzpatrick D. Lower motor neuron circuits and motor control: overview. In: Purves D, Augustine GJ, Fitzpatrick D, editors. Neuroscience. Bethesda: NCBI Bookshelf; 2001.

Frey D, Schneider C, Xu L, Borg J, Spooren W, Caroni P. Early and selective loss of neuromuscular synapse subtypes with low sprouting competence in motoneuron diseases. J Neurosci. 2000;20(7):2534–2542. doi: 10.1523/JNEUROSCI.20-07-02534.2000. PubMed DOI PMC

Gajdusek DC, Salazar AM. Amyotrophic lateral sclerosis and parkinsonian syndromes in high incidence among the Auyu and Jakai people of West New Guinea. Neurology. 1982;32(2):107–126. doi: 10.1212/wnl.32.2.107. PubMed DOI

Gardiner PF. Physiological properties of motoneurons innervating different muscle unit types in rat gastrocnemius. J Neurophysiol. 1993;69(4):1160–1170. doi: 10.1152/jn.1993.69.4.1160. PubMed DOI

Gibson SJ, Polak JM, Katagiri T, Su H, Weller RO, Brownell DB, Holland S, Hughes JT, Kikuyama S, Ball J, et al. A comparison of the distributions of eight peptides in spinal cord from normal controls and cases of motor neurone disease with special reference to Onuf's nucleus. Brain Res. 1988;474(2):255–278. doi: 10.1016/0006-8993(88)90440-4. PubMed DOI

Gizzi M, DiRocco A, Sivak M, Cohen B. Ocular motor function in motor neuron disease. Neurology. 1992;42(5):1037–1046. doi: 10.1212/wnl.42.5.1037. PubMed DOI

Gordon T, Tyreman N, Li S, Putman CT, Hegedus J. Functional over-load saves motor units in the SOD1-G93A transgenic mouse model of amyotrophic lateral sclerosis. Neurobiol Dis. 2010;37(2):412–422. doi: 10.1016/j.nbd.2009.10.021. PubMed DOI

Goutman SA, Hardiman O, Al-Chalabi A, Chio A, Savelieff MG, Kiernan MC, Feldman EL. Recent advances in the diagnosis and prognosis of amyotrophic lateral sclerosis. Lancet Neurol. 2022;21(5):480–493. doi: 10.1016/S1474-4422(21)00465-8. PubMed DOI PMC

Greig A, Donevan SD, Mujtaba TJ, Parks TN, Rao MS. Characterization of the AMPA-activated receptors present on motoneurons. J Neurochem. 2000;74(1):179–191. doi: 10.1046/j.1471-4159.2000.0740179.x. PubMed DOI

Grosskreutz J, Van Den Bosch L, Keller BU. Calcium dysregulation in amyotrophic lateral sclerosis. Cell Calcium. 2010;47(2):165–174. doi: 10.1016/j.ceca.2009.12.002. PubMed DOI

Grossman M. Amyotrophic lateral sclerosis - a multisystem neurodegenerative disorder. Nat Rev Neurol. 2019;15(1):5–6. doi: 10.1038/s41582-018-0103-y. PubMed DOI

Hayashi H, Suga M, Satake M, Tsubaki T. Reduced glycine receptor in the spinal cord in amyotrophic lateral sclerosis. Ann Neurol. 1981;9(3):292–294. doi: 10.1002/ana.410090313. PubMed DOI

Hedlund E, Karlsson M, Osborn T, Ludwig W, Isacson O. Global gene expression profiling of somatic motor neuron populations with different vulnerability identify molecules and pathways of degeneration and protection. Brain. 2010;133(Pt 8):2313–2330. doi: 10.1093/brain/awq167. PubMed DOI PMC

Henderson CE, Camu W, Mettling C, Gouin A, Poulsen K, Karihaloo M, Rullamas J, Evans T, McMahon SB, Armanini MP, et al. Neurotrophins promote motor neuron survival and are present in embryonic limb bud. Nature. 1993;363(6426):266–270. doi: 10.1038/363266a0. PubMed DOI

Henneman E, Somjen G, Carpenter DO. Excitability and inhibitability of motoneurons of different sizes. J Neurophysiol. 1965;28(3):599–620. doi: 10.1152/jn.1965.28.3.599. PubMed DOI

Highstein SM, Karabelas A, Baker R, McCrea RA. Comparison of the morphology of physiologically identified abducens motor and internuclear neurons in the cat: a light microscopic study employing the intracellular injection of horseradish peroxidase. J Comp Neurol. 1982;208(4):369–381. doi: 10.1002/cne.902080407. PubMed DOI

Hochman S, Fedirchuk B, Shefchyk SJ. Membrane electrical properties of external urethral and external anal sphincter somatic motoneurons in the decerebrate cat. Neurosci Lett. 1991;127(1):87–90. doi: 10.1016/0304-3940(91)90901-5. PubMed DOI

Horner SJ, Couturier N, Bruch R, Koch P, Hafner M, Rudolf R. hiPSC-derived schwann cells influence myogenic differentiation in neuromuscular cocultures. Cells. 2021;10(12):3292. doi: 10.3390/cells10123292. PubMed DOI PMC

Inglis FM, Zuckerman KE, Kalb RG. Experience-dependent development of spinal motor neurons. Neuron. 2000;26(2):299–305. doi: 10.1016/s0896-6273(00)81164-2. PubMed DOI

Ingre C, Roos PM, Piehl F, Kamel F, Fang F. Risk factors for amyotrophic lateral sclerosis. Clin Epidemiol. 2015;7:181–193. doi: 10.2147/CLEP.S37505. PubMed DOI PMC

Iwata M, Hirano A. Sparing of the Onufrowicz nucleus in sacral anterior horn lesions. Ann Neurol. 1978;4(3):245–249. doi: 10.1002/ana.410040309. PubMed DOI

Julian TH, Glascow N, Barry ADF, Moll T, Harvey C, Klimentidis YC, Newell M, Zhang S, Snyder MP, Cooper-Knock J, Shaw PJ. Physical exercise is a risk factor for amyotrophic lateral sclerosis: Convergent evidence from Mendelian randomisation, transcriptomics and risk genotypes. EBioMedicine. 2021;68:103397. doi: 10.1016/j.ebiom.2021.103397. PubMed DOI PMC

Kalb RG, Hockfield S. Activity-dependent development of spinal cord motor neurons. Brain Res Brain Res Rev. 1992;17(3):283–289. doi: 10.1016/0165-0173(92)90020-m. PubMed DOI

Kanai K, Shibuya K, Sato Y, Misawa S, Nasu S, Sekiguchi Y, Mitsuma S, Isose S, Fujimaki Y, Ohmori S, Koga S, Kuwabara S. Motor axonal excitability properties are strong predictors for survival in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2012;83(7):734–738. doi: 10.1136/jnnp-2011-301782. PubMed DOI

Kaplan A, Spiller KJ, Towne C, Kanning KC, Choe GT, Geber A, Akay T, Aebischer P, Henderson CE. Neuronal matrix metalloproteinase-9 is a determinant of selective neurodegeneration. Neuron. 2014;81(2):333–348. doi: 10.1016/j.neuron.2013.12.009. PubMed DOI PMC

Katagiri T, Kuzirai T, Nihei K, Honda K, Sasaki H, Polak JM. Immunocytochemical study of Onuf's nucleus in amyotrophic lateral sclerosis. Jpn J Med. 1988;27(1):23–28. doi: 10.2169/internalmedicine1962.27.23. PubMed DOI

Kawamura Y, Dyck PJ, Shimono M, Okazaki H, Tateishi J, Doi H. Morphometric comparison of the vulnerability of peripheral motor and sensory neurons in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol. 1981;40(6):667–675. doi: 10.1097/00005072-198111000-00008. PubMed DOI

Kernell 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)90591-6. PubMed DOI

Kiaei M, Kipiani K, Calingasan NY, Wille E, Chen J, Heissig B, Rafii S, Lorenzl S, Beal MF. Matrix metalloproteinase-9 regulates TNF-alpha and FasL expression in neuronal, glial cells and its absence extends life in a transgenic mouse model of amyotrophic lateral sclerosis. Exp Neurol. 2007;205(1):74–81. doi: 10.1016/j.expneurol.2007.01.036. PubMed DOI

Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, Burrell JR, Zoing MC. Amyotrophic lateral sclerosis. Lancet. 2011;377(9769):942–955. doi: 10.1016/S0140-6736(10)61156-7. PubMed DOI

Kiernan MC, Vucic S, Talbot K, McDermott CJ, Hardiman O, Shefner JM, Al-Chalabi A, Huynh W, Cudkowicz M, Talman P, Van den Berg LH, Dharmadasa T, Wicks P, Reilly C, Turner MR. Improving clinical trial outcomes in amyotrophic lateral sclerosis. Nat Rev Neurol. 2021;17(2):104–118. doi: 10.1038/s41582-020-00434-z. PubMed DOI PMC

Kwak S, Kawahara Y. Deficient RNA editing of GluR2 and neuronal death in amyotropic lateral sclerosis. J Mol Med (berl) 2005;83(2):110–120. doi: 10.1007/s00109-004-0599-z. PubMed DOI

Leal SS, Gomes CM. Calcium dysregulation links ALS defective proteins and motor neuron selective vulnerability. Front Cell Neurosci. 2015;9:225. doi: 10.3389/fncel.2015.00225. PubMed DOI PMC

Lee Y, Morrison BM, Li Y, Lengacher S, Farah MH, Hoffman PN, Liu Y, Tsingalia A, Jin L, Zhang PW, Pellerin L, Magistretti PJ, Rothstein JD. Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature. 2012;487(7408):443–448. doi: 10.1038/nature11314. PubMed DOI PMC

Little CM, Coons KD, Sengelaub DR. Neuroprotective effects of testosterone on the morphology and function of somatic motoneurons following the death of neighboring motoneurons. J Comp Neurol. 2009;512(3):359–372. doi: 10.1002/cne.21885. PubMed DOI PMC

Lobsiger CS, Boillee S, McAlonis-Downes M, Khan AM, Feltri ML, Yamanaka K, Cleveland DW. Schwann cells expressing dismutase active mutant SOD1 unexpectedly slow disease progression in ALS mice. Proc Natl Acad Sci USA. 2009;106(11):4465–4470. doi: 10.1073/pnas.0813339106. PubMed DOI PMC

Lorenzl S, Narr S, Angele B, Krell HW, Gregorio J, Kiaei M, Pfister HW, Beal MF. The matrix metalloproteinases inhibitor Ro 28–2653 [correction of Ro 26–2853] extends survival in transgenic ALS mice. Exp Neurol. 2006;200(1):166–171. doi: 10.1016/j.expneurol.2006.01.026. PubMed DOI

Lorenzo LE, Barbe A, Portalier P, Fritschy JM, Bras H. Differential expression of GABAA and glycine receptors in ALS-resistant vs. ALS-vulnerable motoneurons: possible implications for selective vulnerability of motoneurons. Eur J Neurosci. 2006;23(12):3161–3170. doi: 10.1111/j.1460-9568.2006.04863.x. PubMed DOI

Mackenzie IR, Bigio EH, Ince PG, Geser F, Neumann M, Cairns NJ, Kwong LK, Forman MS, Ravits J, Stewart H, Eisen A, McClusky L, Kretzschmar HA, Monoranu CM, Highley JR, Kirby J, Siddique T, Shaw PJ, Lee VM, Trojanowski JQ. Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol. 2007;61(5):427–434. doi: 10.1002/ana.21147. PubMed DOI

Mannen T, Iwata M, Toyokura Y, Nagashima K. Preservation of a certain motoneurone group of the sacral cord in amyotrophic lateral sclerosis: its clinical significance. J Neurol Neurosurg Psychiatry. 1977;40(5):464–469. doi: 10.1136/jnnp.40.5.464. PubMed DOI PMC

Mannen T, Iwata M, Toyokura Y, Nagashima K. The Onuf's nucleus and the external anal sphincter muscles in amyotrophic lateral sclerosis and Shy-Drager syndrome. Acta Neuropathol. 1982;58(4):255–260. doi: 10.1007/BF00688606. PubMed DOI

Manuel M, Zytnicki D. Molecular and electrophysiological properties of mouse motoneuron and motor unit subtypes. Curr Opin Physiol. 2019;8:23–29. doi: 10.1016/j.cophys.2018.11.008. PubMed DOI PMC

Marin B, Boumediene F, Logroscino G, Couratier P, Babron MC, Leutenegger AL, Copetti M, Preux PM, Beghi E. Variation in worldwide incidence of amyotrophic lateral sclerosis: a meta-analysis. Int J Epidemiol. 2017;46(1):57–74. doi: 10.1093/ije/dyw061. PubMed DOI PMC

Masrori P, Van Damme P. Amyotrophic lateral sclerosis: a clinical review. Eur J Neurol. 2020;27(10):1918–1929. doi: 10.1111/ene.14393. PubMed DOI PMC

McCombe PA, Henderson RD. Effects of gender in amyotrophic lateral sclerosis. Gend Med. 2010;7(6):557–570. doi: 10.1016/j.genm.2010.11.010. PubMed DOI

Mead RJ, Shan N, Reiser HJ, Marshall F, Shaw PJ. Amyotrophic lateral sclerosis: a neurodegenerative disorder poised for successful therapeutic translation. Nat Rev Drug Discov. 2023;22(3):185–212. doi: 10.1038/s41573-022-00612-2. PubMed DOI PMC

Mendell LM. The size principle: a rule describing the recruitment of motoneurons. J Neurophysiol. 2005;93(6):3024–3026. doi: 10.1152/classicessays.00025.2005. PubMed DOI

Mitsumoto H, Kasarskis EJ, Simmons Z. Hastening the diagnosis of amyotrophic lateral sclerosis. Neurology. 2022 doi: 10.1212/WNL.0000000000200799. PubMed DOI

Morisaki Y, Niikura M, Watanabe M, Onishi K, Tanabe S, Moriwaki Y, Okuda T, Ohara S, Murayama S, Takao M, Uchida S, Yamanaka K, Misawa H (2016) Selective expression of osteopontin in ALS-resistant motor neurons is a critical determinant of late phase neurodegeneration mediated by matrix metalloproteinase-9. Sci Rep 6:27354. 10.1038/srep27354 PubMed PMC

Nieto-Gonzalez JL, Moser J, Lauritzen M, Schmitt-John T, Jensen K. Reduced GABAergic inhibition explains cortical hyperexcitability in the wobbler mouse model of ALS. Cereb Cortex. 2011;21(3):625–635. doi: 10.1093/cercor/bhq134. PubMed DOI

Nijssen J, Comley LH, Hedlund E. Motor neuron vulnerability and resistance in amyotrophic lateral sclerosis. Acta Neuropathol. 2017;133(6):863–885. doi: 10.1007/s00401-017-1708-8. PubMed DOI PMC

Okamoto K, Hirai S, Amari M, Iizuka T, Watanabe M, Murakami N, Takatama M. Oculomotor nuclear pathology in amyotrophic lateral sclerosis. Acta Neuropathol. 1993;85(5):458–462. doi: 10.1007/BF00230482. PubMed DOI

Ovsepian SV, Friel DD. The leaner P/Q-type calcium channel mutation renders cerebellar Purkinje neurons hyper-excitable and eliminates Ca2+–Na+ spike bursts. Eur J Neurosci. 2008;27(1):93–103. doi: 10.1111/j.1460-9568.2007.05998.x. PubMed DOI

Ovsepian SV, Vesselkin NP. Serotonergic modulation of synaptic transmission and action potential firing in frog motoneurons. Brain Res. 2006;1102(1):71–77. doi: 10.1016/j.brainres.2006.04.035. PubMed DOI

Ovsepian SV, Vesselkin NP. Wiring prior to firing: the evolutionary rise of electrical and chemical modes of synaptic transmission. Rev Neurosci. 2014;25(6):821–832. doi: 10.1515/revneuro-2014-0037. PubMed DOI

Ovsepian SV, Waxman SG. Gene therapy for chronic pain: emerging opportunities in target-rich peripheral nociceptors. Nat Rev Neurosci. 2023;24(4):252–265. doi: 10.1038/s41583-022-00673-7. PubMed DOI

Ovsepian SV, O'Leary VB, Ntziachristos V, Dolly JO. Circumventing brain barriers: nanovehicles for retroaxonal therapeutic delivery. Trends Mol Med. 2016;22(11):983–993. doi: 10.1016/j.molmed.2016.09.004. PubMed DOI

Ovsepian SV, O'Leary VB, Ayvazyan NM, Al-Sabi A, Ntziachristos V, Dolly JO. Neurobiology and therapeutic applications of neurotoxins targeting transmitter release. Pharmacol Ther. 2019;193:135–155. doi: 10.1016/j.pharmthera.2018.08.016. PubMed DOI

Pabian-Jewula S, Rylski M. Does the functional polymorphism-1562C/T of MMP-9 gene influence brain disorders? Front Cell Neurosci. 2023;17:1110967. doi: 10.3389/fncel.2023.1110967. PubMed DOI PMC

Paganoni S, Macklin EA, Hendrix S, Berry JD, Elliott MA, Maiser S, Karam C, Caress JB, Owegi MA, Quick A, Wymer J, Goutman SA, Heitzman D, Heiman-Patterson T, Jackson CE, Quinn C, Rothstein JD, Kasarskis EJ, Katz J, Jenkins L, Ladha S, Miller TM, Scelsa SN, Vu TH, Fournier CN, Glass JD, Johnson KM, Swenson A, Goyal NA, Pattee GL, Andres PL, Babu S, Chase M, Dagostino D, Dickson SP, Ellison N, Hall M, Hendrix K, Kittle G, McGovern M, Ostrow J, Pothier L, Randall R, Shefner JM, Sherman AV, Tustison E, Vigneswaran P, Walker J, Yu H, Chan J, Wittes J, Cohen J, Klee J, Leslie K, Tanzi RE, Gilbert W, Yeramian PD, Schoenfeld D, Cudkowicz ME. Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis. N Engl J Med. 2020;383(10):919–930. doi: 10.1056/NEJMoa1916945. PubMed DOI PMC

Pastor D, Viso-Leon MC, Botella-Lopez A, Jaramillo-Merchan J, Moraleda JM, Jones J, Martinez S. Bone marrow transplantation in hindlimb muscles of motoneuron degenerative mice reduces neuronal death and improves motor function. Stem Cells Dev. 2013;22(11):1633–1644. doi: 10.1089/scd.2012.0487. PubMed DOI PMC

Perrin S. Preclinical research: make mouse studies work. Nature. 2014;507(7493):423–425. doi: 10.1038/507423a. PubMed DOI

Petri S, Krampfl K, Hashemi F, Grothe C, Hori A, Dengler R, Bufler J. Distribution of GABAA receptor mRNA in the motor cortex of ALS patients. J Neuropathol Exp Neurol. 2003;62(10):1041–1051. doi: 10.1093/jnen/62.10.1041. PubMed DOI

Philips T, Rothstein JD. Glial cells in amyotrophic lateral sclerosis. Exp Neurol. 2014;262(Pt B):111–120. doi: 10.1016/j.expneurol.2014.05.015. PubMed DOI PMC

Picard M, Hepple RT, Burelle Y. Mitochondrial functional specialization in glycolytic and oxidative muscle fibers: tailoring the organelle for optimal function. Am J Physiol Cell Physiol. 2012;302(4):C629–641. doi: 10.1152/ajpcell.00368.2011. PubMed DOI

Plato CC, Garruto RM, Galasko D, Craig UK, Plato M, Gamst A, Torres JM, Wiederholt W. Amyotrophic lateral sclerosis and parkinsonism-dementia complex of Guam: changing incidence rates during the past 60 years. Am J Epidemiol. 2003;157(2):149–157. doi: 10.1093/aje/kwf175. PubMed DOI

Pullen AH, Tucker D, Martin JE. Morphological and morphometric characterisation of Onuf’s nucleus in the spinal cord in man. J Anat. 1997;191(Pt 2):201–213. doi: 10.1046/j.1469-7580.1997.19120201.x. PubMed DOI PMC

Pun S, Santos AF, Saxena S, Xu L, Caroni P. Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF. Nat Neurosci. 2006;9(3):408–419. doi: 10.1038/nn1653. PubMed DOI

Ragagnin AMG, Shadfar S, Vidal M, Jamali MS, Atkin JD. Motor neuron susceptibility in ALS/FTD. Front Neurosci. 2019;13:532. doi: 10.3389/fnins.2019.00532. PubMed DOI PMC

Ramos-Campoy O, Avila-Polo R, Grau-Rivera O, Antonell A, Clarimon J, Rojas-Garcia R, Charif S, Santiago-Valera V, Hernandez I, Aguilar M, Almenar C, Lopez-Villegas D, Bajo L, Pastor P, Van der Zee J, Llado A, Sanchez-Valle R, Gelpi E. Systematic screening of ubiquitin/p62 aggregates in cerebellar cortex expands the neuropathological phenotype of the C9orf72 expansion mutation. J Neuropathol Exp Neurol. 2018;77(8):703–709. doi: 10.1093/jnen/nly047. PubMed DOI

Rando A, Pastor D, Viso-Leon MC, Martinez A, Manzano R, Navarro X, Osta R, Martinez S. Intramuscular transplantation of bone marrow cells prolongs the lifespan of SOD1(G93A) mice and modulates expression of prognosis biomarkers of the disease. Stem Cell Res Ther. 2018;9(1):90. doi: 10.1186/s13287-018-0843-z. PubMed DOI PMC

Reinhard SM, Razak K, Ethell IM. A delicate balance: role of MMP-9 in brain development and pathophysiology of neurodevelopmental disorders. Front Cell Neurosci. 2015;9:280. doi: 10.3389/fncel.2015.00280. PubMed DOI PMC

Rothstein JD, Van Kammen M, Levey AI, Martin LJ, Kuncl RW. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol. 1995;38(1):73–84. doi: 10.1002/ana.410380114. PubMed DOI

Ruegsegger C, Maharjan N, Goswami A, Filezac de L'Etang A, Weis J, Troost D, Heller M, Gut H, Saxena S. Aberrant association of misfolded SOD1 with Na(+)/K(+)ATPase-alpha3 impairs its activity and contributes to motor neuron vulnerability in ALS. Acta Neuropathol. 2016;131(3):427–451. doi: 10.1007/s00401-015-1510-4. PubMed DOI

Russo RE, Hounsgaard J. Dynamics of intrinsic electrophysiological properties in spinal cord neurones. Prog Biophys Mol Biol. 1999;72(4):329–365. doi: 10.1016/s0079-6107(99)00011-5. PubMed DOI

Saini J, Faroni A, Reid AJ, Mouly V, Butler-Browne G, Lightfoot AP, McPhee JS, Degens H, Al-Shanti N. Cross-talk between motor neurons and myotubes via endogenously secreted neural and muscular growth factors. Physiol Rep. 2021;9(8):e14791. doi: 10.14814/phy2.14791. PubMed DOI PMC

Sasaki M. Membrane properties of external urethral and external anal sphincter motoneurones in the cat. J Physiol. 1991;440:345–366. doi: 10.1113/jphysiol.1991.sp018712. PubMed DOI PMC

Sasaki M. Morphological analysis of external urethral and external anal sphincter motoneurones of cat. J Comp Neurol. 1994;349(2):269–287. doi: 10.1002/cne.903490209. PubMed DOI

Saxena S, Cabuy E, Caroni P. A role for motoneuron subtype-selective ER stress in disease manifestations of FALS mice. Nat Neurosci. 2009;12(5):627–636. doi: 10.1038/nn.2297. PubMed DOI

Saxena S, Roselli F, Singh K, Leptien K, Julien JP, Gros-Louis F, Caroni P. Neuroprotection through excitability and mTOR required in ALS motoneurons to delay disease and extend survival. Neuron. 2013;80(1):80–96. doi: 10.1016/j.neuron.2013.07.027. PubMed DOI

Schellino R, Boido M, Vercelli A. The dual nature of Onuf’s nucleus: neuroanatomical features and peculiarities, in health and disease. Front Neuroanat. 2020;14:572013. doi: 10.3389/fnana.2020.572013. PubMed DOI PMC

Scott W, Stevens J, Binder-Macleod SA. Human skeletal muscle fiber type classifications. Phys Ther. 2001;81(11):1810–1816. doi: 10.1093/ptj/81.11.1810. PubMed DOI

Seijffers R, Zhang J, Matthews JC, Chen A, Tamrazian E, Babaniyi O, Selig M, Hynynen M, Woolf CJ, Brown RH., Jr ATF3 expression improves motor function in the ALS mouse model by promoting motor neuron survival and retaining muscle innervation. Proc Natl Acad Sci USA. 2014;111(4):1622–1627. doi: 10.1073/pnas.1314826111. PubMed DOI PMC

Sleigh JN, Rossor AM, Fellows AD, Tosolini AP, Schiavo G. Axonal transport and neurological disease. Nat Rev Neurol. 2019;15(12):691–703. doi: 10.1038/s41582-019-0257-2. PubMed DOI

Spiller KJ, Khan T, Dominique MA, Restrepo CR, Cotton-Samuel D, Levitan M, Jafar-Nejad P, Zhang B, Soriano A, Rigo F, Trojanowski JQ, Lee VM. Reduction of matrix metalloproteinase 9 (MMP-9) protects motor neurons from TDP-43-triggered death in rNLS8 mice. Neurobiol Dis. 2019;124:133–140. doi: 10.1016/j.nbd.2018.11.013. PubMed DOI PMC

Stegenga SL, Kalb RG. Developmental regulation of N-methyl-d-aspartate- and kainate-type glutamate receptor expression in the rat spinal cord. Neuroscience. 2001;105(2):499–507. doi: 10.1016/s0306-4522(01)00143-9. PubMed DOI

Stifani N. Motor neurons and the generation of spinal motor neuron diversity. Front Cell Neurosci. 2014;8:293. doi: 10.3389/fncel.2014.00293. PubMed DOI PMC

Strong MJ, Abrahams S, Goldstein LH, Woolley S, McLaughlin P, Snowden J, Mioshi E, Roberts-South A, Benatar M, HortobaGyi T, Rosenfeld J, Silani V, Ince PG, Turner MR. Amyotrophic lateral sclerosis - frontotemporal spectrum disorder (ALS-FTSD): revised diagnostic criteria. Amyotroph Lateral Scler Frontotemporal Degener. 2017;18(3–4):153–174. doi: 10.1080/21678421.2016.1267768. PubMed DOI PMC

Su WM, Cheng YF, Jiang Z, Duan QQ, Yang TM, Shang HF, Chen YP. Predictors of survival in patients with amyotrophic lateral sclerosis: a large meta-analysis. EBioMedicine. 2021;74:103732. doi: 10.1016/j.ebiom.2021.103732. PubMed DOI PMC

Swinnen B, Robberecht W. The phenotypic variability of amyotrophic lateral sclerosis. Nat Rev Neurol. 2014;10(11):661–670. doi: 10.1038/nrneurol.2014.184. PubMed DOI

Takahashi K. Microglial heterogeneity in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol. 2023;82(2):140–149. doi: 10.1093/jnen/nlac110. PubMed DOI

Taylor AR, Gifondorwa DJ, Newbern JM, Robinson MB, Strupe JL, Prevette D, Oppenheim RW, Milligan CE. Astrocyte and muscle-derived secreted factors differentially regulate motoneuron survival. J Neurosci. 2007;27(3):634–644. doi: 10.1523/JNEUROSCI.4947-06.2007. PubMed DOI PMC

Todd TW, Petrucelli L. Modelling amyotrophic lateral sclerosis in rodents. Nat Rev Neurosci. 2022;23(4):231–251. doi: 10.1038/s41583-022-00564-x. PubMed DOI

Tovar YRLB, Ramirez-Jarquin UN, Lazo-Gomez R, Tapia R. Trophic factors as modulators of motor neuron physiology and survival: implications for ALS therapy. Front Cell Neurosci. 2014;8:61. doi: 10.3389/fncel.2014.00061. PubMed DOI PMC

Tsao W, Jeong YH, Lin S, Ling J, Price DL, Chiang PM, Wong PC. Rodent models of TDP-43: recent advances. Brain Res. 2012;1462:26–39. doi: 10.1016/j.brainres.2012.04.031. PubMed DOI PMC

Tsitkanou S, Lindsay A, Della Gatta P. The role of skeletal muscle in amyotrophic lateral sclerosis: a ‘dying-back’ or ‘dying-forward’ phenomenon? J Physiol. 2019;597(23):5527–5528. doi: 10.1113/JP278835. PubMed DOI

Vafadari B, Salamian A, Kaczmarek L. MMP-9 in translation: from molecule to brain physiology, pathology, and therapy. J Neurochem. 2016;139(Suppl 2):91–114. doi: 10.1111/jnc.13415. PubMed DOI

Valori CF, Brambilla L, Martorana F, Rossi D. The multifaceted role of glial cells in amyotrophic lateral sclerosis. Cell Mol Life Sci. 2014;71(2):287–297. doi: 10.1007/s00018-013-1429-7. PubMed DOI PMC

Van Den Bosch L, Van Damme P, Bogaert E, Robberecht W. The role of excitotoxicity in the pathogenesis of amyotrophic lateral sclerosis. Biochim Biophys Acta. 2006;1762(11–12):1068–1082. doi: 10.1016/j.bbadis.2006.05.002. PubMed DOI

Van Hoecke A, Schoonaert L, Lemmens R, Timmers M, Staats KA, Laird AS, Peeters E, Philips T, Goris A, Dubois B, Andersen PM, Al-Chalabi A, Thijs V, Turnley AM, van Vught PW, Veldink JH, Hardiman O, Van Den Bosch L, Gonzalez-Perez P, Van Damme P, Brown RH, Jr, van den Berg LH, Robberecht W. EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans. Nat Med. 2012;18(9):1418–1422. doi: 10.1038/nm.2901. PubMed DOI

Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, Ganesalingam J, Williams KL, Tripathi V, Al-Saraj S, Al-Chalabi A, Leigh PN, Blair IP, Nicholson G, de Belleroche J, Gallo JM, Miller CC, Shaw CE. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009;323(5918):1208–1211. doi: 10.1126/science.1165942. PubMed DOI PMC

Vercelli A, Cracco C. Effects of prepubertal castration on the spinal motor nucleus of the ischiocavernosus muscle of the rat. Cell Tissue Res. 1990;262(3):551–557. doi: 10.1007/BF00305252. PubMed DOI

Verma M, Lizama BN, Chu CT. Excitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration. Transl Neurodegener. 2022;11(1):3. doi: 10.1186/s40035-021-00278-7. PubMed DOI PMC

Verma S, Khurana S, Vats A, Sahu B, Ganguly NK, Chakraborti P, Gourie-Devi M, Taneja V. Neuromuscular junction dysfunction in amyotrophic lateral sclerosis. Mol Neurobiol. 2022;59(3):1502–1527. doi: 10.1007/s12035-021-02658-6. PubMed DOI

Verslegers M, Lemmens K, Van Hove I, Moons L. Matrix metalloproteinase-2 and -9 as promising benefactors in development, plasticity and repair of the nervous system. Prog Neurobiol. 2013;105:60–78. doi: 10.1016/j.pneurobio.2013.03.004. PubMed DOI

Wainger BJ, Kiskinis E, Mellin C, Wiskow O, Han SS, Sandoe J, Perez NP, Williams LA, Lee S, Boulting G, Berry JD, Brown RH, Jr, Cudkowicz ME, Bean BP, Eggan K, Woolf CJ. Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell Rep. 2014;7(1):1–11. doi: 10.1016/j.celrep.2014.03.019. PubMed DOI PMC

Witzel S, Maier A, Steinbach R, Grosskreutz J, Koch JC, Sarikidi A, Petri S, Gunther R, Wolf J, Hermann A, Prudlo J, Cordts I, Lingor P, Loscher WN, Kohl Z, Hagenacker T, Ruckes C, Koch B, Spittel S, Gunther K, Michels S, Dorst J, Meyer T, Ludolph AC, German Motor Neuron Disease N Safety and Effectiveness of Long-term Intravenous Administration of Edaravone for Treatment of Patients With Amyotrophic Lateral Sclerosis. JAMA Neurol. 2022;79(2):121–130. doi: 10.1001/jamaneurol.2021.4893. PubMed DOI PMC

Yamanaka K, Komine O. The multi-dimensional roles of astrocytes in ALS. Neurosci Res. 2018;126:31–38. doi: 10.1016/j.neures.2017.09.011. PubMed DOI

Yamanaka K, Chun SJ, Boillee S, Fujimori-Tonou N, Yamashita H, Gutmann DH, Takahashi R, Misawa H, Cleveland DW. Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat Neurosci. 2008;11(3):251–253. doi: 10.1038/nn2047. PubMed DOI PMC

Yang T, Wei Q, Li C, Cao B, Ou R, Hou Y, Zhang L, Gu X, Liu K, Lin J, Cheng Y, Jiang Z, Yang J, Kang S, Zhang M, Xiao Y, Zhao B, Chen Y, Chen X, Shang H. Spatial-temporal pattern of propagation in amyotrophic lateral sclerosis and effect on survival: a cohort study. Eur J Neurol. 2022;29(11):3177–3186. doi: 10.1111/ene.15527. PubMed DOI

Zanganeh PF, Barton SK, Lim K, Qian EL, Crombie DE, Bye CR, Turner BJ. Alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor and RNA processing gene dysregulation are early determinants of selective motor neuron vulnerability in a mouse model of amyotrophic lateral sclerosis. Brain Commun. 2022;4(2):fcac081. doi: 10.1093/braincomms/fcac081. PubMed DOI PMC

Zawislak D, Borratynska A, Tomik B, Pera J, Gryz-Kurek E, Szczudlik A. The C(-1562)T polymorphism of the MMP-9 gene and the risk of sporadic amyotrophic lateral sclerosis. Neurol Neurochir Pol. 2009;43(2):121–125. PubMed