Top

Published in:

Open Access 01-06-2017 | Review

Motor neuron vulnerability and resistance in amyotrophic lateral sclerosis

Authors: Jik Nijssen, Laura H. Comley, Eva Hedlund

Published in: Acta Neuropathologica | Issue 6/2017

Abstract

In the fatal disease—amyotrophic lateral sclerosis (ALS)—upper (corticospinal) motor neurons (MNs) and lower somatic MNs, which innervate voluntary muscles, degenerate. Importantly, certain lower MN subgroups are relatively resistant to degeneration, even though pathogenic proteins are typically ubiquitously expressed. Ocular MNs (OMNs), including the oculomotor, trochlear and abducens nuclei (CNIII, IV and VI), which regulate eye movement, persist throughout the disease. Consequently, eye-tracking devices are used to enable paralysed ALS patients (who can no longer speak) to communicate. Additionally, there is a gradient of vulnerability among spinal MNs. Those innervating fast-twitch muscle are most severely affected and degenerate first. MNs innervating slow-twitch muscle can compensate temporarily for the loss of their neighbours by re-innervating denervated muscle until later in disease these too degenerate. The resistant OMNs and the associated extraocular muscles (EOMs) are anatomically and functionally very different from other motor units. The EOMs have a unique set of myosin heavy chains, placing them outside the classical characterization spectrum of all skeletal muscle. Moreover, EOMs have multiple neuromuscular innervation sites per single myofibre. Spinal fast and slow motor units show differences in their dendritic arborisations and the number of myofibres they innervate. These motor units also differ in their functionality and excitability. Identifying the molecular basis of cell-intrinsic pathways that are differentially activated between resistant and vulnerable MNs could reveal mechanisms of selective neuronal resistance, degeneration and regeneration and lead to therapies preventing progressive MN loss in ALS. Illustrating this, overexpression of OMN-enriched genes in spinal MNs, as well as suppression of fast spinal MN-enriched genes can increase the lifespan of ALS mice. Here, we discuss the pattern of lower MN degeneration in ALS and review the current literature on OMN resistance in ALS and differential spinal MN vulnerability. We also reflect upon the non-cell autonomous components that are involved in lower MN degeneration in ALS.

Abhinav K, Stanton B, Johnston C, Hardstaff J, Orrell R, Howard R, Clarke J, Sakel M, Ampong M, Shaw C (2007) Amyotrophic lateral sclerosis in South-East England: a population-based study. Neuroepidemiology 29:44–48PubMedCrossRef

Al-Chalabi A, Andersen PM, Chioza B, Shaw C, Sham PC, Robberecht W, Matthijs G, Camu W, Marklund SL, Forsgren L (1998) Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation share a common founder: evidence for a linked protective factor. Hum Mol Genet 7:2045–2050PubMedCrossRef

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

Allodi I, Comley L, Nichterwitz S, Nizzardo M, Simone C, Benitez JA, Cao M, Corti S, Hedlund E (2016) Differential neuronal vulnerability identifies IGF-2 as a protective factor in ALS. Sci Rep 6:25960. doi:10.1038/srep25960 PubMedPubMedCentralCrossRef

An T, Shi P, Duan W, Zhang S, Yuan P, Li Z, Wu D, Xu Z, Li C, Guo Y (2014) Oxidative stress and autophagic alteration in brainstem of SOD1-G93A mouse model of ALS. Mol Neurobiol 49:1435–1448. doi:10.1007/s12035-013-8623-3 PubMedCrossRef

Andersson E, Tryggvason U, Deng Q, Friling S, Alekseenko Z, Robert B, Perlmann T, Ericson J (2006) Identification of intrinsic determinants of midbrain dopamine neurons. Cell 124:393–405. doi:10.1016/j.cell.2005.10.037 PubMedCrossRef

Atanasio A, Decman V, White D, Ramos M, Ikiz B, Lee HC, Siao CJ, Brydges S, LaRosa E, Bai Y et al (2016) C9orf72 ablation causes immune dysregulation characterized by leukocyte expansion, autoantibody production, and glomerulonephropathy in mice. Sci Rep 6:23204. doi:10.1038/srep23204 PubMedPubMedCentralCrossRef

Beaulieu JM, Nguyen MD, Julien JP (1999) Late onset of motor neurons in mice overexpressing wild-type peripherin. J Cell Biol 147:531–544PubMedPubMedCentralCrossRef

Beers DR, Ho BK, Siklos L, Alexianu ME, Mosier DR, Mohamed AH, Otsuka Y, Kozovska ME, McAlhany RE, Smith RG et al (2001) Parvalbumin overexpression alters immune-mediated increases in intracellular calcium, and delays disease onset in a transgenic model of familial amyotrophic lateral sclerosis. J Neurochem 79:499–509PubMedCrossRef

10.

Bernard-Marissal N, Moumen A, Sunyach C, Pellegrino C, Dudley K, Henderson CE, Raoul C, Pettmann B (2012) Reduced calreticulin levels link endoplasmic reticulum stress and Fas-triggered cell death in motoneurons vulnerable to ALS. J Neurosci 32:4901–4912PubMedCrossRef

11.

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

12.

Beuche W, Yushchenko M, Mader M, Maliszewska M, Felgenhauer K, Weber F (2000) Matrix metalloproteinase-9 is elevated in serum of patients with amyotrophic lateral sclerosis. NeuroReport 11:3419–3422PubMedCrossRef

13.

Bjornskov EK, Norris FH Jr, Mower-Kuby J (1984) Quantitative axon terminal and end-plate morphology in amyotrophic lateral sclerosis. Arch Neurol 41:527–530PubMedCrossRef

14.

Blackburn D, Sargsyan S, Monk PN, Shaw PJ (2009) Astrocyte function and role in motor neuron disease: a future therapeutic target? Glia 57:1251–1264PubMedCrossRef

15.

Boeynaems S, Bogaert E, Van Damme P, Van Den Bosch L (2016) Inside out: the role of nucleocytoplasmic transport in ALS and FTLD. Acta Neuropathol 132:159–173. doi:10.1007/s00401-016-1586-5 PubMedPubMedCentralCrossRef

16.

Boillée S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, Kassiotis G, Kollias G, Cleveland DW (2006) Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312:1389–1392PubMedCrossRef

17.

Brettschneider J, Arai K, Del Tredici K, Toledo JB, Robinson JL, Lee EB, Kuwabara S, Shibuya K, Irwin DJ, Fang L et al (2014) TDP-43 pathology and neuronal loss in amyotrophic lateral sclerosis spinal cord. Acta Neuropathol 128:423–437. doi:10.1007/s00401-014-1299-6 PubMedPubMedCentralCrossRef

18.

Brockington A, Ning K, Heath PR, Wood E, Kirby J, Fusi N, Lawrence N, Wharton SB, Ince PG, Shaw PJ (2013) 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 125:95–109PubMedCrossRef

19.

Brueckner JK, Itkis O, Porter JD (1996) Spatial and temporal patterns of myosin heavy chain expression in developing rat extraocular muscle. J Muscle Res Cell Motil 17:297–312PubMedCrossRef

20.

Bruneteau G, Bauché S, Gonzalez de Aguilar JL, Brochier G, Mandjee N, Tanguy ML, Hussain G, Behin A, Khiami F, Sariali E (2015) Endplate denervation correlates with Nogo-A muscle expression in amyotrophic lateral sclerosis patients. Ann Clin Transl Neurol 2:362–372PubMedPubMedCentralCrossRef

21.

Buller A, Eccles J, Eccles RM (1960) Interactions between motoneurones and muscles in respect of the characteristic speeds of their responses. J Physiol 150:417–439PubMedPubMedCentralCrossRef

22.

Burke R, Dum R, Fleshman J, Glenn L, Lev-Tov A, O’Donovan M, Pinter M (1982) An HRP study of the relation between cell size and motor unit type in cat ankle extensor motoneurons. J Comp Neurol 209:17–28PubMedCrossRef

23.

Burke R, Levine D, Zajac F, Tsairis P, Engel W (1971) Mammalian motor units: physiological-histochemical correlation in three types in cat gastrocnemius. Science 174:709–712PubMedCrossRef

24.

Burke RE, Levine DN, Tsairis P, Zajac FE 3rd (1973) Physiological types and histochemical profiles in motor units of the cat gastrocnemius. J Physiol 234:723–748PubMedPubMedCentralCrossRef

25.

Burke RE, Tsairis P (1973) Anatomy and innervation ratios in motor units of cat gastrocnemius. J Physiol 234:749–765PubMedPubMedCentralCrossRef

26.

Büttner-Ennever JA (2007) Anatomy of the oculomotor system. In: Straube A, Büttner U (eds) Neuro-ophthalmology: neuronal control of eye movements. Karger, Basel

27.

Büttner-Ennever JA, Horn AK, Scherberger H, D’Ascanio P (2001) Motoneurons of twitch and nontwitch extraocular muscle fibers in the abducens, trochlear, and oculomotor nuclei of monkeys. J Comp Neurol 438:318–335PubMedCrossRef

28.

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

29.

Calvo JA, Daniels TG, Wang X, Paul A, Lin J, Spiegelman BM, Stevenson SC, Rangwala SM (2008) Muscle-specific expression of PPARgamma coactivator-1alpha improves exercise performance and increases peak oxygen uptake. J Appl Physiol (1985) 104:1304–1312. doi:10.1152/japplphysiol.01231.2007 CrossRef

30.

Carvalho M, Schwartz MS, Swash M (1995) Involvement of the external anal sphincter in amyotrophic lateral sclerosis. Muscle Nerve 18:848–853. doi:10.1002/mus.880180808 PubMedCrossRef

31.

Chakkalakal JV, Nishimune H, Ruas JL, Spiegelman BM, Sanes JR (2010) Retrograde influence of muscle fibers on their innervation revealed by a novel marker for slow motoneurons. Development 137:3489–3499PubMedPubMedCentralCrossRef

32.

Clement A, Nguyen M, Roberts E, Garcia M, Boillee S, Rule M, McMahon A, Doucette W, Siwek D, Ferrante R (2003) Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302:113–117PubMedCrossRef

33.

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

34.

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

35.

Cullheim S, Fleshman J, Glenn L, Burke R (1987) Membrane area and dendritic structure in type-identified triceps surae alpha motoneurons. J Comp Neurol 255:68–81PubMedCrossRef

36.

Da Cruz S, Parone PA, Lopes VS, Lillo C, McAlonis-Downes M, Lee SK, Vetto AP, Petrosyan S, Marsala M, Murphy AN (2012) Elevated PGC-1α activity sustains mitochondrial biogenesis and muscle function without extending survival in a mouse model of inherited ALS. Cell Metab 15:778–786PubMedPubMedCentralCrossRef

37.

De La Cruz RR, Escudero M, Delgado-Garcia JM (1989) Behaviour of medial rectus motoneurons in the alert cat. Eur J Neurosci 1:288–295CrossRef

38.

DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, Nicholson AM, Finch NA, Flynn H, Adamson J (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72:245–256PubMedPubMedCentralCrossRef

39.

Delestrée N, Manuel M, Iglesias C, Elbasiouny SM, Heckman C, Zytnicki D (2014) Adult spinal motoneurones are not hyperexcitable in a mouse model of inherited amyotrophic lateral sclerosis. J Physiol 592:1687–1703PubMedPubMedCentralCrossRef

40.

Deng Q, Andersson E, Hedlund E, Alekseenko Z, Coppola E, Panman L, Millonig JH, Brunet JF, Ericson J, Perlmann T (2011) Specific and integrated roles of Lmx1a, Lmx1b and Phox2a in ventral midbrain development. Development 138:3399–3408. doi:10.1242/dev.065482 PubMedCrossRef

41.

Dengler R, Konstanzer A, Küther G, Hesse S, Wolf W, Strupplerdr A (1990) Amyotrophic lateral sclerosis: macro-EMG and twitch forces of single motor units. Muscle Nerve 13:545–550PubMedCrossRef

42.

Dewil M, dela Cruz VF, Van Den Bosch L, Robberecht W (2007) Inhibition of p38 mitogen activated protein kinase activation and mutant SOD1(G93A)-induced motor neuron death. Neurobiol Dis 26:332–341. doi:10.1016/j.nbd.2006.12.023 PubMedCrossRef

43.

Di Giorgio FP, Boulting GL, Bobrowicz S, Eggan KC (2008) Human embryonic stem cell-derived motor neurons are sensitive to the toxic effect of glial cells carrying an ALS-causing mutation. Cell Stem Cell 3:637–648PubMedCrossRef

44.

Di Giorgio FP, Carrasco MA, Siao MC, Maniatis T, Eggan K (2007) Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nat Neurosci 10:608–614PubMedPubMedCentralCrossRef

45.

Dobrowolny G, Aucello M, Rizzuto E, Beccafico S, Mammucari C, Boncompagni S, Belia S, Wannenes F, Nicoletti C, Del Prete Z et al (2008) Skeletal muscle is a primary target of SOD1G93A-mediated toxicity. Cell Metab 8:425–436. doi:10.1016/j.cmet.2008.09.002 PubMedCrossRef

46.

Dopeso-Reyes IG, Rico AJ, Roda E, Sierra S, Pignataro D, Lanz M, Sucunza D, Chang-Azancot L, Lanciego JL (2014) Calbindin content and differential vulnerability of midbrain efferent dopaminergic neurons in macaques. Front Neuroanat 8:146. doi:10.3389/fnana.2014.00146 PubMedPubMedCentralCrossRef

47.

Dubreuil V, Hirsch MR, Pattyn A, Brunet JF, Goridis C (2000) The Phox2b transcription factor coordinately regulates neuronal cell cycle exit and identity. Development 127:5191–5201PubMed

48.

Enoka RM (1995) Morphological features and activation patterns of motor units. J Clin Neurophysiol 12:538–559PubMedCrossRef

49.

Eustache I, Seyfritz N, Gueritaud JP (1994) Effects of insulin-like growth factors on organotypic cocultures of embryonic rat brainstem slices and skeletal muscle fibers. Brain Res Dev Brain Res 81:284–292PubMedCrossRef

50.

Ferri AL, Lin W, Mavromatakis YE, Wang JC, Sasaki H, Whitsett JA, Ang SL (2007) Foxa1 and Foxa2 regulate multiple phases of midbrain dopaminergic neuron development in a dosage-dependent manner. Development 134:2761–2769. doi:10.1242/dev.000141 PubMedCrossRef

51.

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

52.

Fischer LR, Culver DG, Tennant P, Davis AA, Wang M, Castellano-Sanchez A, Khan J, Polak MA, Glass JD (2004) Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp Neurol 185:232–240PubMedCrossRef

53.

Fogh I, Rijsdijk F, Andersen PM, Sham PC, Knight J, Neale B, McKenna-Yasek D, Silani V, Brown RH Jr, Powell JF (2007) Age at onset in sod1-mediated amyotrophic lateral sclerosis shows familiality. Neurogenetics 8:235–236PubMedCrossRef

54.

Frakes AE, Ferraiuolo L, Haidet-Phillips AM, Schmelzer L, Braun L, Miranda CJ, Ladner KJ, Bevan AK, Foust KD, Godbout JP (2014) Microglia induce motor neuron death via the classical NF-κB pathway in amyotrophic lateral sclerosis. Neuron 81:1009–1023PubMedPubMedCentralCrossRef

55.

Frey D, Schneider C, Xu L, Borg J, Spooren W, Caroni P (2000) Early and selective loss of neuromuscular synapse subtypes with low sprouting competence in motoneuron diseases. J Neurosci 20:2534–2542PubMed

56.

Fuchs AF, Scudder CA, Kaneko CR (1988) Discharge patterns and recruitment order of identified motoneurons and internuclear neurons in the monkey abducens nucleus. J Neurophysiol 60:1874–1895PubMed

57.

Gardiner PF (1993) Physiological properties of motoneurons innervating different muscle unit types in rat gastrocnemius. J Neurophysiol 69:1160–1170PubMed

58.

Genc B, Jara JH, Schultz MC, Manuel M, Stanford MJ, Gautam M, Klessner JL, Sekerkova G, Heller DB, Cox GA et al (2016) Absence of UCHL 1 function leads to selective motor neuropathy. Ann Clin Transl Neurol 3:331–345. doi:10.1002/acn3.298 PubMedPubMedCentralCrossRef

59.

Ginhoux F, Lim S, Hoeffel G, Low D, Huber T (2013) Origin and differentiation of microglia. Front Cell Neurosci 7:45. doi:10.3389/fncel.2013.00045 PubMedPubMedCentralCrossRef

60.

Gitler AD, Tsuiji H (2016) There has been an awakening: emerging mechanisms of C9orf72 mutations in FTD/ALS. Brain Res 1647:19–29. doi:10.1016/j.brainres.2016.04.004 PubMedCrossRef

61.

Gizzi M, DiRocco A, Sivak M, Cohen B (1992) Ocular motor function in motor neuron disease. Neurology 42:1037–1046PubMedCrossRef

62.

Gould TW, Buss RR, Vinsant S, Prevette D, Sun W, Knudson CM, Milligan CE, Oppenheim RW (2006) Complete dissociation of motor neuron death from motor dysfunction by Bax deletion in a mouse model of ALS. J Neurosci 26:8774–8786. doi:10.1523/jneurosci.2315-06.2006 PubMedCrossRef

63.

Grant K, Gueritaud JP, Horcholle-Bossavit G, Tyc-Dumont S (1979) Morphological characteristics of lateral rectus motoneurones shown by intracellular injection of HRP. J Physiol (Paris) 75:513–519

64.

Greig A, Donevan SD, Mujtaba TJ, Parks TN, Rao MS (2000) Characterization of the AMPA-Activated Receptors Present on Motoneurons. J Neurochem 74:179–191PubMedCrossRef

65.

Grosskreutz J, Van Den Bosch L, Keller BU (2010) Calcium dysregulation in amyotrophic lateral sclerosis. Cell Calcium 47:165–174PubMedCrossRef

66.

Gueritaud JP, Horcholle-Bossavit G, Jami L, Thiesson D, Tyc-Dumont S (1985) Resistance to glycogen depletion of motor units in the cat rectus lateralis muscle. Exp Brain Res 60:542–550PubMedCrossRef

67.

Hadzipasic M, Tahvildari B, Nagy M, Bian M, Horwich AL, McCormick DA (2014) Selective degeneration of a physiological subtype of spinal motor neuron in mice with SOD1-linked ALS. Proc Natl Acad Sci USA 111:16883–16888PubMedPubMedCentralCrossRef

68.

Haidet-Phillips AM, Hester ME, Miranda CJ, Meyer K, Braun L, Frakes A, Song S, Likhite S, Murtha MJ, Foust KD (2011) Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. Nat Biotechnol 29:824–828PubMedPubMedCentralCrossRef

69.

Hall ED, Oostveen JA, Gurney ME (1998) Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS. Glia 23:249–256PubMedCrossRef

70.

Hanyu N, Oguchi K, Yanagisawa N, Tsukagoshi H (1982) Degeneration and regeneration of ventral root motor fibers in amyotrophic lateral sclerosis. Morphometric studies of cervical ventral roots. J Neurol Sci 55:99–115PubMedCrossRef

71.

Hasan KB, Agarwala S, Ragsdale CW (2010) PHOX2A regulation of oculomotor complex nucleogenesis. Development 137:1205–1213. doi:10.1242/dev.041251 PubMedPubMedCentralCrossRef

72.

Hedlund E, Isacson O (2008) ALS model glia can mediate toxicity to motor neurons derived from human embryonic stem cells. Cell Stem Cell 3:575–576PubMedCrossRef

73.

Hedlund E, Karlsson M, Osborn T, Ludwig W, Isacson O (2010) Global gene expression profiling of somatic motor neuron populations with different vulnerability identify molecules and pathways of degeneration and protection. Brain 133:2313–2330PubMedPubMedCentralCrossRef

74.

Hegedus J, Putman C, Gordon T (2007) Time course of preferential motor unit loss in the SOD1^G93A mouse model of amyotrophic lateral sclerosis. Neurobiol Dis 28:154–164PubMedCrossRef

75.

Heiman-Patterson TD, Sher RB, Blankenhorn EA, Alexander G, Deitch JS, Kunst CB, Maragakis N, Cox G (2011) Effect of genetic background on phenotype variability in transgenic mouse models of amyotrophic lateral sclerosis: a window of opportunity in the search for genetic modifiers. Amyotroph Lateral Scler 12:79–86PubMedCrossRef

76.

Henneman E, Somjen G, Carpenter DO (1965) Excitability and inhibitibility of motoneurons of different sizes. J Neurophysiol 28:599–620PubMed

77.

Hennig R, Lømo T (1984) Discharge patterns of presumed FF, FR and S motor units during normal motor behaviour in the rat. Acta Physiol Scand 121:A28

78.

Hideyama T, Yamashita T, Suzuki T, Tsuji S, Higuchi M, Seeburg PH, Takahashi R, Misawa H, Kwak S (2010) Induced loss of ADAR2 engenders slow death of motor neurons from Q/R site-unedited GluR2. J Neurosci 30:11917–11925. doi:10.1523/jneurosci.2021-10.2010 PubMedCrossRef

79.

Highstein SM, Karabelas A, Baker R, McCrea RA (1982) 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 208:369–381. doi:10.1002/cne.902080407 PubMedCrossRef

80.

Hochstim C, Deneen B, Lukaszewicz A, Zhou Q, Anderson DJ (2008) Identification of positionally distinct astrocyte subtypes whose identities are specified by a homeodomain code. Cell 133:510–522PubMedPubMedCentralCrossRef

81.

Hollyday M, Hamburger V (1976) Reduction of the naturally occurring motor neuron loss by enlargement of the periphery. J Comp Neurol 170:311–320. doi:10.1002/cne.901700304 PubMedCrossRef

82.

Huang C, Tong J, Bi F, Zhou H, Xia XG (2012) Mutant TDP-43 in motor neurons promotes the onset and progression of ALS in rats. J Clin Invest 122:107–118. doi:10.1172/jci59130 PubMedCrossRef

83.

Ilieva HS, Yamanaka K, Malkmus S, Kakinohana O, Yaksh T, Marsala M, Cleveland DW (2008) Mutant dynein (Loa) triggers proprioceptive axon loss that extends survival only in the SOD1 ALS model with highest motor neuron death. Proc Natl Acad Sci USA 105:12599–12604. doi:10.1073/pnas.0805422105 PubMedPubMedCentralCrossRef

84.

Jaarsma D, Teuling E, Haasdijk ED, De Zeeuw CI, Hoogenraad CC (2008) Neuron-specific expression of mutant superoxide dismutase is sufficient to induce amyotrophic lateral sclerosis in transgenic mice. J Neurosci 28:2075–2088. doi:10.1523/jneurosci.5258-07.2008 PubMedCrossRef

85.

Jacoby J, Ko K, Weiss C, Rushbrook JI (1990) Systematic variation in myosin expression along extraocular muscle fibres of the adult rat. J Muscle Res Cell Motil 11:25–40PubMedCrossRef

86.

Joksimovic M, Yun BA, Kittappa R, Anderegg AM, Chang WW, Taketo MM, McKay RD, Awatramani RB (2009) Wnt antagonism of Shh facilitates midbrain floor plate neurogenesis. Nat Neurosci 12:125–131. doi:10.1038/nn.2243 PubMedCrossRef

87.

Kanai K, Shibuya K, Sato Y, Misawa S, Nasu S, Sekiguchi Y, Mitsuma S, Isose S, Fujimaki Y, Ohmori S (2012) Motor axonal excitability properties are strong predictors for survival in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 83:734–738PubMedCrossRef

88.

Kang SH, Fukaya M, Yang JK, Rothstein JD, Bergles DE (2010) NG2⁺ CNS glial progenitors remain committed to the oligodendrocyte lineage in postnatal life and following neurodegeneration. Neuron 68:668–681PubMedPubMedCentralCrossRef

89.

Kang SH, Li Y, Fukaya M, Lorenzini I, Cleveland DW, Ostrow LW, Rothstein JD, Bergles DE (2013) Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis. Nat Neurosci 16:571–579PubMedPubMedCentralCrossRef

90.

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

91.

Kaspar BK, Llado J, Sherkat N, Rothstein JD, Gage FH (2003) Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model. Science 301:839–842. doi:10.1126/science.1086137 PubMedCrossRef

92.

Kawamura Y, Dyck PJ, Shimono M, Okazaki H, Doi J, Tateishi H (1981) Morphometric comparison of the vulnerability of peripheral motor and sensory neurons in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 40:667–675PubMedCrossRef

93.

Kernell D, Zwaagstra B (1981) Input conductance axonal conduction velocity and cell size among hindlimb motoneurones of the cat. Brain Res 204:311–326PubMedCrossRef

94.

Kiaei M, Kipiani K, Calingasan NY, Wille E, Chen J, Heissig B, Rafii S, Lorenzl S, Beal MF (2007) 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 205:74–81. doi:10.1016/j.expneurol.2007.01.036 PubMedCrossRef

95.

Kiernan JA, Hudson AJ (1993) Changes in shapes of surviving motor neurons in amyotrophic lateral sclerosis. Brain 116(Pt 1):203–215PubMedCrossRef

96.

Kiernan JA, Hudson AJ (1991) Changes in sizes of cortical and lower motor neurons in amyotrophic lateral sclerosis. Brain 114(Pt 2):843–853PubMedCrossRef

97.

Kim W, Kim J-S, Lee K-S, Gwoun Y-J, Kim J-M, Lee K-H (2007) Anticipation and phenotypic heterogeneity in Korean familial amyotrophic lateral sclerosis with superoxide dismutase 1 gene mutation. J Clin Neurol 3:38–44PubMedPubMedCentralCrossRef

98.

Kubota M, Sakakihara Y, Uchiyama Y, Nara A, Nagata T, Nitta H, Ishimoto K, Oka A, Horio K, Yanagisawa M (2000) New ocular movement detector system as a communication tool in ventilator-assisted Werdnig–Hoffmann disease. Dev Med Child Neurol 42:61–64PubMedCrossRef

99.

Kuo JJ, Schonewille M, Siddique T, Schults AN, Fu R, Bär PR, Anelli R, Heckman CJ, Kroese AB (2004) Hyperexcitability of cultured spinal motoneurons from presymptomatic ALS mice. J Neurophysiol 91:571–575PubMedCrossRef

100.

Kwak S, Kawahara Y (2005) Deficient RNA editing of GluR2 and neuronal death in amyotropic lateral sclerosis. J Mol Med 83:110–120PubMedCrossRef

101.

Kwiatkowski TJ, Bosco D, Leclerc A, Tamrazian E, Vanderburg C, Russ C, Davis A, Gilchrist J, Kasarskis E, Munsat T (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323:1205–1208PubMedCrossRef

102.

Lagier-Tourenne C, Polymenidou M, Cleveland DW (2010) TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration. Hum Mol Genet 19:R46–R64. doi:10.1093/hmg/ddq137 PubMedPubMedCentralCrossRef

103.

Laslo P, Lipski J, Nicholson LF, Miles GB, Funk GD (2001) GluR2 AMPA receptor subunit expression in motoneurons at low and high risk for degeneration in amyotrophic lateral sclerosis. Exp Neurol 169:461–471PubMedCrossRef

104.

Lautenschlaeger J, Prell T, Grosskreutz J (2012) Endoplasmic reticulum stress and the ER mitochondria calcium cycle in amyotrophic lateral sclerosis. Amyotroph Lateral Scler 13:166–177PubMedCrossRef

105.

Lawyer T Jr, Netsky MG (1953) Amyotrophic lateral sclerosis. AMA Arch Neurol Psychiatry 69:171–192PubMedCrossRef

106.

Lee Y, Morrison BM, Li Y, Lengacher S, Farah MH, Hoffman PN, Liu Y, Tsingalia A, Jin L, Zhang PW et al (2012) Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 487:443–448. doi:10.1038/nature11314 PubMedPubMedCentralCrossRef

107.

Leroy F, d’Incamps BL, Imhoff-Manuel RD, Zytnicki D (2014) Early intrinsic hyperexcitability does not contribute to motoneuron degeneration in amyotrophic lateral sclerosis. eLife 3:e04046PubMedCentralCrossRef

108.

Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Bennett ML, Munch AE, Chung WS, Peterson TC et al (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature. doi:10.1038/nature21029 (Epub ahead of print) PubMed

109.

Lim GP, Backstrom JR, Cullen MJ, Miller CA, Atkinson RD, Tokes ZA (1996) Matrix metalloproteinases in the neocortex and spinal cord of amyotrophic lateral sclerosis patients. J Neurochem 67:251–259PubMedCrossRef

110.

Lin J, Wu H, Tarr PT, Zhang C-Y, Wu Z, Boss O, Michael LF, Puigserver P, Isotani E, Olson EN (2002) Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibres. Nature 418:797–801PubMedCrossRef

111.

Liu KX, Edwards B, Lee S, Finelli MJ, Davies B, Davies KE, Oliver PL (2015) Neuron-specific antioxidant OXR1 extends survival of a mouse model of amyotrophic lateral sclerosis. Brain 138:1167–1181. doi:10.1093/brain/awv039 PubMedPubMedCentralCrossRef

112.

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

113.

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

114.

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

115.

Mancuso R, Martinez-Muriana A, Leiva T, Gregorio D, Ariza L, Morell M, Esteban-Perez J, Garcia-Redondo A, Calvo AC, Atencia-Cibreiro G et al (2016) Neuregulin-1 promotes functional improvement by enhancing collateral sprouting in SOD1(G93A) ALS mice and after partial muscle denervation. Neurobiol Dis 95:168–178. doi:10.1016/j.nbd.2016.07.023 PubMedCrossRef

116.

Maragakis NJ, Rothstein JD (2006) Mechanisms of disease: astrocytes in neurodegenerative disease. Nat Clin Pract Neuro 2:679–689CrossRef

117.

Marchetto MC, Muotri AR, Mu Y, Smith AM, Cezar GG, Gage FH (2008) Non-cell-autonomous effect of human SOD1 G37R astrocytes on motor neurons derived from human embryonic stem cells. Cell Stem Cell 3:649–657PubMedCrossRef

118.

Martin E, Cazenave W, Cattaert D, Branchereau P (2013) Embryonic alteration of motoneuronal morphology induces hyperexcitability in the mouse model of amyotrophic lateral sclerosis. Neurobiol Dis 54:116–126. doi:10.1016/j.nbd.2013.02.011 PubMedCrossRef

119.

Maselli RA, Wollman RL, Leung C, Distad B, Palombi S, Richman DP, Salazar-Grueso EF, Roos RP (1993) Neuromuscular transmission in amyotrophic lateral sclerosis. Muscle Nerve 16:1193–1203PubMedCrossRef

120.

Mavlyutov TA, Guo L-W, Epstein ML, Ruoho AE (2015) Role of the sigma-1 receptor in amyotrophic lateral sclerosis (ALS). J Pharmacol Sci 127:10–16PubMedPubMedCentralCrossRef

121.

McMahon AP, Bradley A (1990) The Wnt-1 (int-1) proto-oncogene is required for development of a large region of the mouse brain. Cell 62:1073–1085PubMedCrossRef

122.

Mendell LM (2005) The size principle: a rule describing the recruitment of motoneurons. J Neurophysiol 93:3024–3026PubMedCrossRef

123.

Mertens J, Paquola AC, Ku M, Hatch E, Bohnke L, Ladjevardi S, McGrath S, Campbell B, Lee H, Herdy JR et al (2015) Directly reprogrammed human neurons retain aging-associated transcriptomic signatures and reveal age-related nucleocytoplasmic defects. Cell Stem Cell 17:705–718. doi:10.1016/j.stem.2015.09.001 PubMedCrossRef

124.

Mesci P, Zaidi S, Lobsiger CS, Millecamps S, Escartin C, Seilhean D, Sato H, Mallat M, Boillee S (2015) System xC- is a mediator of microglial function and its deletion slows symptoms in amyotrophic lateral sclerosis mice. Brain 138:53–68. doi:10.1093/brain/awu312 PubMedCrossRef

125.

Meyer K, Ferraiuolo L, Miranda CJ, Likhite S, McElroy S, Renusch S, Ditsworth D, Lagier-Tourenne C, Smith RA, Ravits J (2014) Direct conversion of patient fibroblasts demonstrates non-cell autonomous toxicity of astrocytes to motor neurons in familial and sporadic ALS. Proc Natl Acad Sci USA 111:829–832PubMedCrossRef

126.

Millecamps S, Nicolle D, Ceballos-Picot I, Mallet J, Barkats M (2001) Synaptic sprouting increases the uptake capacities of motoneurons in amyotrophic lateral sclerosis mice. Proc Natl Acad Sci USA 98:7582–7587. doi:10.1073/pnas.131031098 PubMedPubMedCentralCrossRef

127.

Miller TM, Kim SH, Yamanaka K, Hester M, Umapathi P, Arnson H, Rizo L, Mendell JR, Gage FH, Cleveland DW et al (2006) Gene transfer demonstrates that muscle is not a primary target for non-cell-autonomous toxicity in familial amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 103:19546–19551. doi:10.1073/pnas.0609411103 PubMedPubMedCentralCrossRef

128.

Mitchell JC, McGoldrick P, Vance C, Hortobagyi T, Sreedharan J, Rogelj B, Tudor EL, Smith BN, Klasen C, Miller CC et al (2013) Overexpression of human wild-type FUS causes progressive motor neuron degeneration in an age- and dose-dependent fashion. Acta Neuropathol 125:273–288. doi:10.1007/s00401-012-1043-z PubMedCrossRef

129.

Mizuno Y, Fujita Y, Takatama M, Okamoto K (2012) Comparison of phosphorylated TDP-43-positive inclusions in oculomotor neurons in patients with non-ALS and ALS disorders. J Neurol Sci 315:20–25. doi:10.1016/j.jns.2011.12.012 PubMedCrossRef

130.

Molofsky AV, Kelley KW, Tsai HH, Redmond SA, Chang SM, Madireddy L, Chan JR, Baranzini SE, Ullian EM, Rowitch DH (2014) Astrocyte-encoded positional cues maintain sensorimotor circuit integrity. Nature 509:189–194. doi:10.1038/nature13161 PubMedPubMedCentralCrossRef

131.

Mong J, Panman L, Alekseenko Z, Kee N, Stanton LW, Ericson J, Perlmann T (2014) Transcription factor-induced lineage programming of noradrenaline and motor neurons from embryonic stem cells. Stem Cells 32:609–622. doi:10.1002/stem.1585 PubMedCrossRef

132.

Morisaki Y, Niikura M, Watanabe M, Onishi K, Tanabe S, Moriwaki Y, Okuda T, Ohara S, Murayama S, Takao M et al (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. doi:10.1038/srep27354 PubMedPubMedCentralCrossRef

133.

Muller D, Cherukuri P, Henningfeld K, Poh CH, Wittler L, Grote P, Schluter O, Schmidt J, Laborda J, Bauer SR et al (2014) Dlk1 promotes a fast motor neuron biophysical signature required for peak force execution. Science 343:1264–1266. doi:10.1126/science.1246448 PubMedCrossRef

134.

Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wichterle H, Przedborski S (2007) Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci 10:615–622PubMedPubMedCentralCrossRef

135.

Nardo G, Iennaco R, Fusi N, Heath PR, Marino M, Trolese MC, Ferraiuolo L, Lawrence N, Shaw PJ, Bendotti C (2013) Transcriptomic indices of fast and slow disease progression in two mouse models of amyotrophic lateral sclerosis. Brain 136:3305–3332. doi:10.1093/brain/awt250 PubMedCrossRef

136.

Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133PubMedCrossRef

137.

Nimchinsky EA, Young WG, Yeung G, Shah RA, Gordon JW, Bloom FE, Morrison JH, Hof PR (2000) Differential vulnerability of oculomotor, facial, and hypoglossal nuclei in G86R superoxide dismutase transgenic mice. J Comp Neurol 416:112–125PubMedCrossRef

138.

Ozdinler PH, Benn S, Yamamoto TH, Guzel M, Brown RH Jr, Macklis JD (2011) Corticospinal motor neurons and related subcerebral projection neurons undergo early and specific neurodegeneration in hSOD1G(9)(3)A transgenic ALS mice. J Neurosci 31:4166–4177. doi:10.1523/jneurosci.4184-10.2011 PubMedPubMedCentralCrossRef

139.

Pattyn A, Morin X, Cremer H, Goridis C, Brunet JF (1997) Expression and interactions of the two closely related homeobox genes Phox2a and Phox2b during neurogenesis. Development 124:4065–4075PubMed

140.

Perez-Balaguer A, Puelles E, Wurst W, Martinez S (2009) Shh dependent and independent maintenance of basal midbrain. Mech Dev 126:301–313. doi:10.1016/j.mod.2009.03.001 PubMedCrossRef

141.

Piccione EA, Sletten DM, Staff NP, Low PA (2015) Autonomic system and amyotrophic lateral sclerosis. Muscle Nerve 51:676–679. doi:10.1002/mus.24457 PubMedPubMedCentralCrossRef

142.

Porter JD (2002) Extraocular muscle: cellular adaptations for a diverse functional repertoire. Ann N Y Acad Sci 956:7–16PubMedCrossRef

143.

Porter JD, Khanna S, Kaminski HJ, Rao JS, Merriam AP, Richmonds CR, Leahy P, Li J, Andrade FH (2001) Extraocular muscle is defined by a fundamentally distinct gene expression profile. Proc Natl Acad Sci USA 98:12062–12067. doi:10.1073/pnas.211257298 PubMedPubMedCentralCrossRef

144.

Prakash N, Brodski C, Naserke T, Puelles E, Gogoi R, Hall A, Panhuysen M, Echevarria D, Sussel L, Weisenhorn DM et al (2006) A Wnt1-regulated genetic network controls the identity and fate of midbrain-dopaminergic progenitors in vivo. Development 133:89–98. doi:10.1242/dev.02181 PubMedCrossRef

145.

Prakash N, Puelles E, Freude K, Trumbach D, Omodei D, Di Salvio M, Sussel L, Ericson J, Sander M, Simeone A et al (2009) Nk6–1 controls the identity and fate of red nucleus and oculomotor neurons in the mouse midbrain. Development 136:2545–2555. doi:10.1242/dev.031781 PubMedPubMedCentralCrossRef

146.

Puelles E, Acampora D, Lacroix E, Signore M, Annino A, Tuorto F, Filosa S, Corte G, Wurst W, Ang SL et al (2003) Otx dose-dependent integrated control of antero-posterior and dorso-ventral patterning of midbrain. Nat Neurosci 6:453–460. doi:10.1038/nn1037 PubMed

147.

Pun S, Santos AF, Saxena S, Xu L, Caroni P (2006) Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF. Nat Neurosci 9:408–419PubMedCrossRef

148.

Renton AE, Majounie E, Waite A, Simón-Sánchez J, Rollinson S, Gibbs JR, Schymick JC, Laaksovirta H, Van Swieten JC, Myllykangas L (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72:257–268PubMedPubMedCentralCrossRef

149.

Riascos D, de Leon D, Baker-Nigh A, Nicholas A, Yukhananov R, Bu J, Wu CK, Geula C (2011) Age-related loss of calcium buffering and selective neuronal vulnerability in Alzheimer’s disease. Acta Neuropathol 122:565–576. doi:10.1007/s00401-011-0865-4 PubMedPubMedCentralCrossRef

150.

Rinholm JE, Hamilton NB, Kessaris N, Richardson WD, Bergersen LH, Attwell D (2011) Regulation of oligodendrocyte development and myelination by glucose and lactate. J Neurosci 31:538–548. doi:10.1523/jneurosci.3516-10.2011 PubMedPubMedCentralCrossRef

151.

Rizzo F, Riboldi G, Salani S, Nizzardo M, Simone C, Corti S, Hedlund E (2014) Cellular therapy to target neuroinflammation in amyotrophic lateral sclerosis. Cell Mol Life Sci 71:999–1015PubMedCrossRef

152.

Robinson DA (1970) Oculomotor unit behavior in the monkey. J Neurophysiol 33:393–403PubMed

153.

Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O’Regan JP, Deng HX et al (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:59–62. doi:10.1038/362059a0 PubMedCrossRef

154.

Rossi AC, Mammucari C, Argentini C, Reggiani C, Schiaffino S (2010) Two novel/ancient myosins in mammalian skeletal muscles: MYH14/7b and MYH15 are expressed in extraocular muscles and muscle spindles. J Physiol 588:353–364. doi:10.1113/jphysiol.2009.181008 PubMedCrossRef

155.

Rouaux C, Panteleeva I, Rene F, Gonzalez de Aguilar JL, Echaniz-Laguna A, Dupuis L, Menger Y, Boutillier AL, Loeffler JP (2007) Sodium valproate exerts neuroprotective effects in vivo through CREB-binding protein-dependent mechanisms but does not improve survival in an amyotrophic lateral sclerosis mouse model. J Neurosci 27:5535–5545. doi:10.1523/jneurosci.1139-07.2007 PubMedCrossRef

156.

Ruegsegger C, Maharjan N, Goswami A, de L’Etang AF, Weis J, Troost D, Heller M, Gut H, Saxena S (2015) Aberrant association of misfolded SOD1 with Na/KATPase-alpha3 impairs its activity and contributes to motor neuron vulnerability in ALS. Acta Neuropathol. doi:10.1007/s00401-015-1510-4 PubMed

157.

Rushbrook J, Weiss C, Ko K, Feuerman M, Carleton S, Ing A, Jacoby J (1994) Identification of alpha-cardiac myosin heavy chain mRNA and protein in extraocular muscle of the adult rabbit. J Muscle Res Cell Motil 15:505–515PubMedCrossRef

158.

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

159.

Saxena S, Roselli F, Singh K, Leptien K, Julien J-P, Gros-Louis F, Caroni P (2013) Neuroprotection through excitability and mTOR required in ALS motoneurons to delay disease and extend survival. Neuron 80:80–96PubMedCrossRef

160.

Schaefer AM, Sanes JR, Lichtman JW (2005) A compensatory subpopulation of motor neurons in a mouse model of amyotrophic lateral sclerosis. J Comp Neurol 490:209–219. doi:10.1002/cne.20620 PubMedCrossRef

161.

Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, Ransohoff RM, Greenberg ME, Barres BA, Stevens B (2012) Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74:691–705PubMedPubMedCentralCrossRef

162.

Schoser BG, Blottner D (1999) Matrix metalloproteinases MMP-2, MMP-7 and MMP-9 in denervated human muscle. NeuroReport 10:2795–2797PubMedCrossRef

163.

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

164.

Sharma A, Lyashchenko AK, Lu L, Nasrabady SE, Elmaleh M, Mendelsohn M, Nemes A, Tapia JC, Mentis GZ, Shneider NA (2016) ALS-associated mutant FUS induces selective motor neuron degeneration through toxic gain of function. Nat Commun 7:10465. doi:10.1038/ncomms10465 PubMedPubMedCentralCrossRef

165.

Silva D, Dikkes P, Barnes M, Lopez MF (2009) Decreased motoneuron survival in Igf2 null mice after sciatic nerve transection. NeuroReport 20:1414–1418. doi:10.1097/WNR.0b013e328330b735 PubMedCrossRef

166.

Sloan SA, Barres BA (2014) Mechanisms of astrocyte development and their contributions to neurodevelopmental disorders. Curr Opin Neurobiol 27:75–81PubMedPubMedCentralCrossRef

167.

Spencer R, Porter J (1988) Structural organization of the extraocular muscles. Rev Oculomot Res 2:33–79PubMed

168.

Spiller KJ, Cheung CJ, Restrepo CR, Kwong LK, Stieber AM, Trojanowski JQ, Lee VM (2016) Selective motor neuron resistance and recovery in a new inducible mouse model of TDP-43 proteinopathy. J Neurosci 36:7707–7717. doi:10.1523/jneurosci.1457-16.2016 PubMedCrossRef

169.

Sudria-Lopez E, Koppers M, de Wit M, van der Meer C, Westeneng HJ, Zundel CA, Youssef SA, Harkema L, de Bruin A, Veldink JH et al (2016) Full ablation of C9orf72 in mice causes immune system-related pathology and neoplastic events but no motor neuron defects. Acta Neuropathol. doi:10.1007/s00401-016-1581-x PubMedPubMedCentral

170.

Sun S, Ling SC, Qiu J, Albuquerque CP, Zhou Y, Tokunaga S, Li H, Qiu H, Bui A, Yeo GW et al (2015) ALS-causative mutations in FUS/TLS confer gain and loss of function by altered association with SMN and U1-snRNP. Nat Commun 6:6171. doi:10.1038/ncomms7171 PubMedPubMedCentralCrossRef

171.

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

172.

Syed N, Kim HA (2010) Soluble neuregulin and Schwann cell myelination: a therapeutic potential for improving remyelination of adult axons. Mol Cell Pharmacol 2:161–167. doi:10.4255/mcpharmacol.10.22 PubMedPubMedCentral

173.

Tateno M, Sadakata H, Tanaka M, Itohara S, Shin RM, Miura M, Masuda M, Aosaki T, Urushitani M, Misawa H et al (2004) Calcium-permeable AMPA receptors promote misfolding of mutant SOD1 protein and development of amyotrophic lateral sclerosis in a transgenic mouse model. Hum Mol Genet 13:2183–2196. doi:10.1093/hmg/ddh246 PubMedCrossRef

174.

Tjust AE, Brannstrom T, Pedrosa-Domellof F (2012) Unaffected motor endplate occupancy in eye muscles of ALS G93A mouse model. Front Biosci (Schol Ed) 4:1547–1555

175.

Torres-Torrelo J, Torres B, Carrascal L (2014) Modulation of the input-output function by GABAA receptor-mediated currents in rat oculomotor nucleus motoneurons. J Physiol 592:5047–5064. doi:10.1113/jphysiol.2014.276576 PubMedPubMedCentralCrossRef

176.

Torres-Torrelo J, Rodríguez-Rosell D, Nunez-Abades P, Carrascal L, Torres B (2012) Glutamate modulates the firing rate in oculomotor nucleus motoneurons as a function of the recruitment threshold current. J Physiol 590:3113–3127PubMedPubMedCentralCrossRef

177.

Ulfhake B, Kellerth JO (1981) A quantitative light microscopic study of the dendrites of cat spinal α-motoneurons after intracellular staining with horseradish peroxidase. J Comp Neurol 202:571–583. doi:10.1002/cne.902020409 PubMedCrossRef

178.

Ullian EM, Christopherson KS, Barres BA (2004) Role for glia in synaptogenesis. Glia 47:209–216PubMedCrossRef

179.

Valdez G, Tapia JC, Lichtman JW, Fox MA, Sanes JR (2012) Shared resistance to aging and ALS in neuromuscular junctions of specific muscles. PLoS One 7:e34640PubMedPubMedCentralCrossRef

180.

Van Den Bosch L, Schwaller B, Vleminckx V, Meijers B, Stork S, Ruehlicke T, Van Houtte E, Klaassen H, Celio MR, Missiaen L et al (2002) Protective effect of parvalbumin on excitotoxic motor neuron death. Exp Neurol 174:150–161. doi:10.1006/exnr.2001.7858 CrossRef

181.

Van Den Bosch L, Van Damme P, Bogaert E, Robberecht W (2006) The role of excitotoxicity in the pathogenesis of amyotrophic lateral sclerosis. BBA Mol Basis Dis 1762:1068–1082CrossRef

182.

Van Hoecke A, Schoonaert L, Lemmens R, Timmers M, Staats KA, Laird AS, Peeters E, Philips T, Goris A, Dubois B (2012) EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans. Nat Med 18:1418–1422PubMedCrossRef

183.

Vance C, Rogelj B, Hortobágyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323:1208–1211PubMedPubMedCentralCrossRef

184.

Venugopal S, Hsiao C-F, Sonoda T, Wiedau-Pazos M, Chandler SH (2015) Homeostatic dysregulation in membrane properties of masticatory motoneurons compared with oculomotor neurons in a mouse model for amyotrophic lateral sclerosis. J Neurosci 35:707–720PubMedPubMedCentralCrossRef

185.

Vinsant S, Mansfield C, Jimenez-Moreno R, Del Gaizo Moore V, Yoshikawa M, Hampton TG, Prevette D, Caress J, Oppenheim RW, Milligan C (2013) Characterization of early pathogenesis in the SOD1(G93A) mouse model of ALS: part II, results and discussion. Brain Behav 3:431–457. doi:10.1002/brb3.142 PubMedPubMedCentralCrossRef

186.

Wainger BJ, Kiskinis E, Mellin C, Wiskow O, Han SS, Sandoe J, Perez NP, Williams LA, Lee S, Boulting G (2014) Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell Rep 7:1–11PubMedPubMedCentralCrossRef

187.

Walker AK, Spiller KJ, Ge G, Zheng A, Xu Y, Zhou M, Tripathy K, Kwong LK, Trojanowski JQ, Lee VM (2015) Functional recovery in new mouse models of ALS/FTLD after clearance of pathological cytoplasmic TDP-43. Acta Neuropathol 130:643–660. doi:10.1007/s00401-015-1460-x PubMedPubMedCentralCrossRef

188.

Wang L, Pytel P, Feltri ML, Wrabetz L, Roos RP (2012) Selective knockdown of mutant SOD1 in Schwann cells ameliorates disease in G85R mutant SOD1 transgenic mice. Neurobiol Dis 48:52–57. doi:10.1016/j.nbd.2012.05.014 PubMedCrossRef

189.

Wasicky R, Horn AK, Buttner-Ennever JA (2004) Twitch and nontwitch motoneuron subgroups in the oculomotor nucleus of monkeys receive different afferent projections. J Comp Neurol 479:117–129. doi:10.1002/cne.20296 PubMedCrossRef

190.

Wen X, Westergard T, Pasinelli P, Trotti D (2017) Pathogenic determinants and mechanisms of ALS/FTD linked to hexanucleotide repeat expansions in the C9orf72 gene. Neurosci Lett 636:16–26. doi:10.1016/j.neulet.2016.09.007 PubMedCrossRef

191.

Wieczorek DF, Periasamy M, Butler-Browne GS, Whalen RG, Nadal-Ginard B (1985) Co-expression of multiple myosin heavy chain genes, in addition to a tissue-specific one, in extraocular musculature. J Cell Biol 101:618–629PubMedCrossRef

192.

Wong M, Martin LJ (2010) Skeletal muscle-restricted expression of human SOD1 causes motor neuron degeneration in transgenic mice. Hum Mol Genet 19:2284–2302. doi:10.1093/hmg/ddq106 PubMedPubMedCentralCrossRef

193.

Woodhoo A, Sommer L (2008) Development of the Schwann cell lineage: from the neural crest to the myelinated nerve. Glia 56:1481–1490. doi:10.1002/glia.20723 PubMedCrossRef

194.

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

195.

Ye W, Shimamura K, Rubenstein JL, Hynes MA, Rosenthal A (1998) FGF and Shh signals control dopaminergic and serotonergic cell fate in the anterior neural plate. Cell 93:755–766PubMedCrossRef

196.

Zhao W, Varghese M, Yemul S, Pan Y, Cheng A, Marano P, Hassan S, Vempati P, Chen F, Qian X (2011) Peroxisome proliferator activator receptor gamma coactivator-1alpha (PGC-1α) improves motor performance and survival in a mouse model of amyotrophic lateral sclerosis. Mol Neurodegener 6:51PubMedPubMedCentralCrossRef

197.

Zhou Y, Liu D, Kaminski HJ (2010) Myosin heavy chain expression in mouse extraocular muscle: more complex than expected. Invest Ophthalmol Vis Sci 51:6355–6363. doi:10.1167/iovs.10-5937 PubMedPubMedCentralCrossRef

198.

Zhou Y, Liu D, Kaminski HJ (2011) Pitx2 regulates myosin heavy chain isoform expression and multi-innervation in extraocular muscle. J Physiol 589:4601–4614. doi:10.1113/jphysiol.2011.207076 PubMedPubMedCentralCrossRef

199.

Zimmermann L, Morado-Diaz CJ, Davis-Lopez de Carrizosa MA, de la Cruz RR, May PJ, Streicher J, Pastor AM, Blumer R (2013) Axons giving rise to the palisade endings of feline extraocular muscles display motor features. J Neurosci 33:2784–2793. doi:10.1523/jneurosci.4116-12.2013 PubMedPubMedCentralCrossRef

Title: Motor neuron vulnerability and resistance in amyotrophic lateral sclerosis
Authors: Jik Nijssen
Laura H. Comley
Eva Hedlund
Publication date: 01-06-2017
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 6/2017
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-017-1708-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Motor neuron vulnerability and resistance in amyotrophic lateral sclerosis

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 6/2017

Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis

Cryptic exon incorporation occurs in Alzheimer’s brain lacking TDP-43 inclusion but exhibiting nuclear clearance of TDP-43

Proteomic differences in amyloid plaques in rapidly progressive and sporadic Alzheimer’s disease

Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis

Genome-wide, high-content siRNA screening identifies the Alzheimer’s genetic risk factor FERMT2 as a major modulator of APP metabolism

Marginal vitamin A deficiency facilitates Alzheimer’s pathogenesis