1 Saxena, S. & Caroni, P. Selective neuronal vulnerability in neurodegenerative diseases: from stressor thresholds to degeneration. Neuron 71, 35–48 (2011).

2 Frey, D. et al. Early and selective loss of neuromuscular synapse subtypes with low sprouting competence in motoneuron diseases. J. Neurosci. 20, 2534–2542 (2000).

3 Fischer, L. R. et al. Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp. Neurol. 185, 232–240 (2004).

4 Ringholz, G. M. et al. Prevalence and patterns of cognitive impairment in sporadic ALS. Neurology 65, 586–590 (2005).

5 Andersen, P. M. & Al-Chalabi, A. Clinical genetics of amyotrophic lateral sclerosis: what do we really know? Nature Rev. Neurol. 7, 603–615 (2011).

6 Williamson, T. L. & Cleveland, D. W. Slowing of axonal transport is a very early event in the toxicity of ALS-linked SOD1 mutants to motor neurons. Nature Neurosci. 2, 50–56 (1999).

7 Amendola, J. et al. Altered sensorimotor development in a transgenic mouse model of amyotrophic lateral sclerosis. Eur. J. Neurosci. 20, 2822–2826 (2004).

8 van Zundert, B. et al. Neonatal neuronal circuitry shows hyperexcitable disturbance in a mouse model of the adult-onset neurodegenerative disease amyotrophic lateral sclerosis. J. Neurosci. 28, 10864–10874 (2008).

9 Bories, C. et al. Early electrophysiological abnormalities in lumbar motoneurons in a transgenic mouse model of amyotrophic lateral sclerosis. Eur. J. Neurosci. 25, 451–459 (2007).

10 Regal, L. et al. The G93C mutation in superoxide dismutase 1: clinicopathologic phenotype and prognosis. Arch. Neurol. 63, 262–267 (2006).

11 Philips, T. & Robberecht, W. Neuroinflammation in amyotrophic lateral sclerosis: role of glial activation in motor neuron disease. Lancet Neurol. 10, 253–263 (2011).

12 Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130–133 (2006). This is this first study to link ALS with FTLD, and identifies TDP43 as a major disease protein in the ubiquitin-positive, tau-negative inclusions of affected tissue of patients with ALS and patients with FTLD. The subsequent identification of C9ORF72 as a major disease-causing protein in both ALS and FTLD confirmed this concept.

13 Bendotti, C. et al. Dysfunction of constitutive and inducible ubiquitin-proteasome system in amyotrophic lateral sclerosis: implication for protein aggregation and immune response. Prog. Neurobiol. 97, 101–126 (2012).

14 Basso, M. et al. Insoluble mutant SOD1 is partly oligoubiquitinated in amyotrophic lateral sclerosis mice. J. Biol. Chem. 281, 33325–33335 (2006).

15 Chen, S. et al. Autophagy dysregulation in amyotrophic lateral sclerosis. Brain Pathol. 22, 110–116 (2012).

16 Sasaki, S. Autophagy in spinal cord motor neurons in sporadic amyotrophic lateral sclerosis. J. Neuropathol. Exp. Neurol. 70, 349–359 (2011).

17 Morimoto, N. et al. Increased autophagy in transgenic mice with a G93A mutant SOD1 gene. Brain Res. 1167, 112–117 (2007).

18 Saxena, S., E. Cabuy & Caroni, P. A role for motoneuron subtype-selective ER stress in disease manifestations of FALS mice. Nature Neurosci. 12, 627–636 (2009). The authors describe the early involvement of endoplasmic reticulum stress in the selective vulnerability of motor neurons. Endoplasmic reticulum stress is one of the earliest pathological changes associated with motor neurons in ALS. It occurs well before muscular denervation and axonal retraction.

19 Ilieva, H., Polymenidou, M. & Cleveland, D. W. Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J. Cell Biol. 187, 761–772 (2009).

20 Ezzi, S. A., Urushitani, M. & Julien, J. P. Wild-type superoxide dismutase acquires binding and toxic properties of ALS-linked mutant forms through oxidation. J. Neurochem. 102, 170–178 (2007).

21 Bosco, D. A. et al. Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS. Nature Neurosci. 13, 1396–1403 (2010). This paper suggests that wild-type SOD1 can acquire a specific pathological conformation that is shared with mutant SOD1 and could therefore be implicated in SALS, indicating that there is a SOD1-dependent pathway common to both SALS and FALS. These findings are still controversial, as they could not be reproduced by other studies (see reference 23).

22 Rakhit, R. et al. Oxidation-induced misfolding and aggregation of superoxide dismutase and its implications for amyotrophic lateral sclerosis. J. Biol. Chem. 277, 47551–47556 (2002).

23 Brotherton, T. E. et al. Localization of a toxic form of superoxide dismutase 1 protein to pathologically affected tissues in familial ALS. Proc. Natl Acad. Sci. USA 109, 5505–5510 (2012).

24 Deng, H. X. et al. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 477, 211–215 (2011). This is the first paper to describe UBQLN2 mutations as a cause of ALS. Interestingly, ubiquilin pathology was not restricted to patients with ALS who had UBQLN2 mutations but also to SALS cases in which UBQLN2-positive inclusions could be identified in the brain and spinal cord.

25 Bertram, L. et al. Family-based association between Alzheimer's disease and variants in UBQLN1. N. Engl. J. Med. 352, 884–894 (2005).

26 Ko, H. S. et al. Ubiquilin interacts with ubiquitylated proteins and proteasome through its ubiquitin-associated and ubiquitin-like domains. FEBS Lett. 566, 110–114 (2004).

27 Williams, K. L. et al. UBQLN2/ubiquilin 2 mutation and pathology in familial amyotrophic lateral sclerosis. Neurobiol. Aging 33, 2527.e3–2527.e10 (2012).

28 Synofzik, M. et al. Screening in ALS and FTD patients reveals 3 novel UBQLN2 mutations outside the PXX domain and a pure FTD phenotype. Neurobiol. Aging 33, 2949.e13–2949.e17 (2012).

29 Fecto, F. et al. SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch. Neurol. 68, 1440–1446 (2011).

30 Johnson, J. O. et al. Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68, 857–864 (2010).

31 Watts, G. D. et al. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nature Genet. 36, 377–381 (2004).

32 Meyer, H., Bug, M. & Bremer, S. Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system. Nature Cell Biol. 14, 117–123 (2012).

33 Song, C., Wang, Q. & Li, C. C. ATPase activity of p97-valosin-containing protein (VCP). D2 mediates the major enzyme activity, and D1 contributes to the heat-induced activity. J. Biol. Chem. 278, 3648–3655 (2003).

34 Parkinson, N. et al. ALS phenotypes with mutations in CHMP2B (charged multivesicular body protein 2B). Neurology 67, 1074–1077 (2006).

35 Maruyama, H. et al. Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465, 223–226 (2010).

36 Chow, C. Y. et al. Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS. Am. J. Hum. Genet. 84, 85–88 (2009).

37 Filimonenko, M. et al. Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease. J. Cell Biol. 179, 485–500 (2007).

38 Skibinski, G. et al. Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nature Genet. 37, 806–808 (2005).

39 Zhu, G. et al. Optineurin negatively regulates TNFα induced NF-κB activation by competing with NEMO for ubiquitinated RIP. Curr. Biol. 17, 1438–1443 (2007).

40 Deng, H. X. et al. Differential involvement of optineurin in amyotrophic lateral sclerosis with or without SOD1 mutations. Arch. Neurol. 68, 1057–1061 (2011).

41 Gary, J. D. et al. Regulation of Fab1 phosphatidylinositol 3-phosphate 5-kinase pathway by Vac7 protein and Fig4 a polyphosphoinositide phosphatase family member. Mol. Biol. Cell 13, 1238–1251 (2002).

42 Kraft, C., Peter, M. & Hofmann, K. Selective autophagy: ubiquitin-mediated recognition and beyond. Nature Cell Biol. 12, 836–841 (2010).

43 Tashiro, Y. et al. Motor neuron-specific disruption of proteasomes, but not autophagy, replicates amyotrophic lateral sclerosis. J. Biol. Chem. 287, 42984–42994 (2012).

44 Sendtner, M. Therapy development in spinal muscular atrophy. Nature Neurosci. 13, 795–799 (2010).

45 Burghes, A. H. & Beattie, C. E. Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick? Nature Rev. Neurosci. 10, 597–609 (2009).

46 Schrank, B. et al. Inactivation of the survival motor neuron gene, a candidate gene for human spinal muscular atrophy, leads to massive cell death in early mouse embryos. Proc. Natl Acad. Sci. USA 94, 9920–9925 (1997).

47 Wang, H. F. et al. Valosin-containing protein and neurofibromin interact to regulate dendritic spine density. J. Clin. Invest. 121, 4820–4837 (2011).

48 Lemmens, R. et al. RNA metabolism and the pathogenesis of motor neuron diseases. Trends Neurosci. 33, 249–258 (2010).

49 Sreedharan, J. et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319, 1668–1672 (2008).

50 Rutherford, N. J. et al. Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis. PLoS Genet. 4, e1000193 (2008).

51 Lee, E. B., Lee, V. M. & Trojanowski, J. Q. Gains or losses: molecular mechanisms of TDP-43-mediated neurodegeneration. Nature Rev. Neurosci. 13, 38–50 (2012).

52 Buratti, E. et al. Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping. EMBO J. 20, 1774–1784 (2001).

53 Buratti, E. et al. Nuclear factor TDP-43 binds to the polymorphic TG repeats in CFTR intron 8 and causes skipping of exon 9: a functional link with disease penetrance. Am. J. Hum. Genet. 74, 1322–1325 (2004).

54 Polymenidou, M. et al. Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nature Neurosci. 14, 459–468 (2011). These authors used iCLIP (individual-nucleotide resolution UV cross-linking and immunoprecipitation) in combination with high-throughput sequencing to find binding sites for TDP43 in >6,000 genes, including some long pre-mRNAs that are enriched in motor neurons. Upon TDP43 depletion, changes in specific RNA abundance and splicing patterns were measured, which could potentially underlie the loss of TDP43 function in ALS.

55 Tollervey, J. R. et al. Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nature Neurosci. 14, 452–458 (2011).

56 Kawahara, Y. & Mieda-Sato, A. TDP-43 promotes microRNA biogenesis as a component of the Drosha and Dicer complexes. Proc. Natl Acad. Sci. USA 109, 3347–3352 (2012).

57 Buratti, E. et al. Nuclear factor TDP-43 can affect selected microRNA levels. FEBS J. 277, 2268–2281 (2010).

58 Dewey, C. M. et al. TDP-43 is directed to stress granules by sorbitol, a novel physiological osmotic and oxidative stressor. Mol. Cell. Biol. 31, 1098–1108 (2011).

59 McDonald, K. K. et al. TAR DNA-binding protein 43 (TDP-43) regulates stress granule dynamics via differential regulation of G3BP and TIA-1. Hum. Mol. Genet. 20, 1400–1410 (2011).

60 Shorter, J. The mammalian disaggregase machinery: Hsp110 synergizes with Hsp70 and Hsp40 to catalyze protein disaggregation and reactivation in a cell-free system. PLoS ONE 6, e26319 (2011).

61 Dewey, C. M. et al. TDP-43 aggregation in neurodegeneration: are stress granules the key? Brain Res. 1462, 16–25 (2012).

62 Kedersha, N. et al. Dynamic shuttling of TIA-1 accompanies the recruitment of mRNA to mammalian stress granules. J. Cell Biol. 151, 1257–1268 (2000).

63 Kedersha, N. L. et al. RNA-binding proteins TIA-1 and TIAR link the phosphorylation of eIF-2α to the assembly of mammalian stress granules. J. Cell Biol. 147, 1431–1442 (1999).

64 Kimball, S. R. et al. Mammalian stress granules represent sites of accumulation of stalled translation initiation complexes. Am. J. Physiol. Cell Physiol. 284, C273–C284 (2003).

65 Liu-Yesucevitz, L. et al. Tar DNA binding protein-43 (TDP-43) associates with stress granules: analysis of cultured cells and pathological brain tissue. PLoS ONE 5, e13250 (2010).

66 Johnson, B. S. et al. TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity. J. Biol. Chem. 284, 20329–20339 (2009).

67 Arnold, E. S. et al. ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43. Proc. Natl Acad. Sci. USA 110, E736–E745 (2013).

68 Elden, A. C. et al. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466, 1069–1075 (2010). Using a yeast toxicity screen, the authors found that a yeast orthologue for ATXN2 is a strong modifier of TDP43-mediated toxicity. In patients with ALS, intermediate-length ATXN2 poly-Q expansions were associated with disease, providing a link between ALS and other polyQ diseases such as myotonic dystrophy type 1 and SCA2.

69 Voigt, A. et al. TDP-43-mediated neuron loss in vivo requires RNA-binding activity. PLoS ONE 5, e12247 (2010).

70 Ritson, G. P. et al. TDP-43 mediates degeneration in a novel Drosophila model of disease caused by mutations in VCP/p97. J. Neurosci. 30, 7729–7739 (2010).

71 Ayala, Y. M. et al. TDP-43 regulates its mRNA levels through a negative feedback loop. EMBO J. 30, 277–288 (2011).

72 Chartier-Harlin, M. C. et al. α-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 364, 1167–1169 (2004).

73 Rovelet-Lecrux, A. et al. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nature Genet. 38, 24–26 (2006).

74 Swarup, V. et al. Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor κB-mediated pathogenic pathways. J. Exp. Med. 208, 2429–2447 (2011).

75 Sanpei, K. et al. Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nature Genet. 14, 277–284 (1996).

76 Van Damme, P. et al. Expanded ATXN2 CAG repeat size in ALS identifies genetic overlap between ALS and SCA2. Neurology 76, 2066–2072 (2011).

77 Conforti, F. L. et al. Ataxin-1 and ataxin-2 intermediate-length PolyQ expansions in amyotrophic lateral sclerosis. Neurology 79, 2315–2320 (2012).

78 Lee, T. et al. Ataxin-2 intermediate-length polyglutamine expansions in European ALS patients. Hum. Mol. Genet. 20, 1697–1700 (2011).

79 Gispert, S. et al. The modulation of amyotrophic lateral sclerosis risk by ataxin-2 intermediate polyglutamine expansions is a specific effect. Neurobiol. Dis. 45, 356–361 (2012).

80 Yu, Z. et al. PolyQ repeat expansions in ATXN2 associated with ALS are CAA interrupted repeats. PLoS ONE 6, e17951 (2011).

81 Hart, M. P. & Gitler, A. D. ALS-associated ataxin 2 polyQ expansions enhance stress-induced caspase 3 activation and increase TDP-43 pathological modifications. J. Neurosci. 32, 9133–9142 (2012).

82 Armakola, M. et al. Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models. Nature Genet. 44, 1302–1309 (2012). Following up on ATXN2 as a disease modifier for TDP43-mediated toxicity, the authors report the role of the DBR1 as a contributor to TDP43-mediated toxicity. Subsequent to splicing events, when intronic lariats are no longer processed by DBR1, the lariats sequester TDP43 and prevent TDP43 from exerting its neurotoxic effects.

83 Bertolotti, A. et al. hTAF(II)68, a novel RNA/ssDNA-binding protein with homology to the pro-oncoproteins TLS/FUS and EWS is associated with both TFIID and RNA polymerase II. EMBO J. 15, 5022–5031 (1996).

84 Kwiatkowski, T. J. Jr et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323, 1205–1208 (2009).

85 Sun, Z. et al. Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS. PLoS Biol 9, e1000614 (2011).

86 Lagier-Tourenne, C. M. Polymenidou & Cleveland, D. W. TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration. Hum. Mol. Genet. 19, R46–R64 (2010).

87 Vance, C. et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323, 1208–1211 (2009).

88 Waibel, S., Neumann, M., Rabe, M., Meyer, T. & Ludolph, A. C. Novel missense and truncating mutations in FUS/TLS in familial ALS. Neurology 75, 815–817 (2010).

89 Huang, E. J. et al. Extensive FUS-immunoreactive pathology in juvenile amyotrophic lateral sclerosis with basophilic inclusions. Brain Pathol. 20, 1069–1076 (2010).

90 Baumer, D. et al. Juvenile ALS with basophilic inclusions is a FUS proteinopathy with FUS mutations. Neurology 75, 611–618 (2010).

91 Aoki, N. et al. Localization of fused in sarcoma (FUS) protein to the post-synaptic density in the brain. Acta Neuropathol. 124, 383–394 (2012).

92 Zinszner, H. et al. TLS (FUS) binds RNA in vivo and engages in nucleo-cytoplasmic shuttling. J. Cell Sci. 110, 1741–1750 (1997).

93 Dormann, D. et al. ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import. EMBO J. 29, 2841–2857 (2010). This paper elegantly shows that FUS mutations are localized in the NLS and that they lead to impaired nuclear import and FUS accumulation in the cytoplasm, where it associates with stress granules.

94 Dormann, D. et al. Arginine methylation next to the PY-NLS modulates Transportin binding and nuclear import of FUS. EMBO J. 31, 4258–4275 (2012).

95 Lagier-Tourenne, C. et al. Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs. Nature Neurosci. 15, 1488–1497 (2012). Similar to the study on RNA targets for TDP43, this study focuses on RNA targets for FUS and found many genes to be differentially expressed and/or spliced upon FUS depletion. Interestingly, upon both FUS and TDP43 depletion, the abundance of some long pre-mRNAs involved in neuronal integrity was reduced, suggesting loss-of-function as a common component of motor neuron disease upon FUS or TDP43 dysregulation.

96 Dormann, D. & Haass, C. TDP-43 and FUS: a nuclear affair. Trends Neurosci. 34, 339–348 (2011).

97 Farg, M. A. et al. Ataxin-2 interacts with FUS and intermediate-length polyglutamine expansions enhance FUS-related pathology in amyotrophic lateral sclerosis. Hum. Mol. Genet. 22, 717–728 (2012).

98 Couthouis, J. et al. A yeast functional screen predicts new candidate ALS disease genes. Proc. Natl Acad. Sci. USA 108, 20881–20890 (2011).

99 Couthouis, J. et al. Evaluating the role of the FUS/TLS-related gene EWSR1 in amyotrophic lateral sclerosis. Hum. Mol. Genet. 21, 2899–2911 (2012).

100 Polymenidou, M. & Cleveland, D. W. The seeds of neurodegeneration: prion-like spreading in ALS. Cell 147, 498–508 (2011).

101 King, O. D., Gitler, A. D. & Shorter, J. The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease. Brain Res. 1462, 61–80 (2012).

102 Cushman, M. et al. Prion-like disorders: blurring the divide between transmissibility and infectivity. J. Cell Sci. 123, 1191–1201 (2010).

103 Munch, C., O'Brien, J. & Bertolotti, A. Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells. Proc. Natl Acad. Sci. USA 108, 3548–3553 (2011).

104 Grad, L. I. et al. Intermolecular transmission of superoxide dismutase 1 misfolding in living cells. Proc. Natl Acad. Sci. USA 108, 16398–16403 (2011).

105 Ravits, J. M. & La Spada, A. R. ALS motor phenotype heterogeneity, focality, and spread: deconstructing motor neuron degeneration. Neurology 73, 805–811 (2009).

106 Luk, K. C. et al. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338, 949–953 (2012). This paper shows that non-transgenic mice inoculated with synthetic α-synuclein fibrils acquire Parkinson-like Lewy body disease, which propagates from cell to cell, causing dopaminergic loss of the substantia nigra pars compacta. This could be an interesting disease mechanism through which prion domain-containing proteins,such as TDP43 and FUS, which are known to be causative of ALS, are similarly propagating, causing selective motor neuron disease.

107 DeJesus-Hernandez, M. et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245–256 (2011).

108 Renton, A. E. et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257–268 (2011). References 107 and 108 are the first to describe a hexanucleotide repeat in the 5′ non-coding sequence of C9ORF72 as a cause of ALS and FTLD. Reference 107 also describes the presence of intranuclear repeat-containing RNA foci.

109 Gijselinck, I. et al. A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet Neurol. 11, 54–65 (2012).

110 Majounie, E. et al. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol. 11, 323–330 (2012).

111 Dobson-Stone, C. et al. C9ORF72 repeat expansion in clinical and neuropathologic frontotemporal dementia cohorts. Neurology 79, 995–1001 (2012).

112 Levine, T. P., Daniels, R. D., Gatta, A. T., Wong, L. H. & Hayes, M. J. The product of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFs. Bioinformatics 29, 499–503 (2013).

113 Chio, A. et al. Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72. Brain 135, 784–793 (2012).

114 Millecamps, S. et al. Phenotype difference between ALS patients with expanded repeats in C9ORF72 and patients with mutations in other ALS-related genes. J. Med. Genet. 49, 258–263 (2012).

115 Brettschneider, J. et al. Pattern of ubiquilin pathology in ALS and FTLD indicates presence of C9ORF72 hexanucleotide expansion. Acta Neuropathol. 123, 825–839 (2012).

116 Byrne, S. et al. Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study. Lancet Neurol. 11, 232–240 (2012).

117 Snowden, J. S. et al. Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain 135, 693–708 (2012).

118 Pearson, J. P. et al. Familial frontotemporal dementia with amyotrophic lateral sclerosis and a shared haplotype on chromosome 9p. J. Neurol. 258, 647–655 (2011).

119 van Blitterswijk, M. et al. Evidence for an oligogenic basis of amyotrophic lateral sclerosis. Hum. Mol. Genet. 21, 3776–3784 (2012).

120 van Blitterswijk, M. Dejesus-Hernandez, M. & Rademakers, R. How do C9ORF72 repeat expansions cause amyotrophic lateral sclerosis and frontotemporal dementia: can we learn from other noncoding repeat expansion disorders? Curr. Opin. Neurol. 25, 689–700 (2012).

121 Hsiung, G. Y. et al. Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p. Brain 135, 709–722 (2012).

122 Campuzano, V. et al. Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271, 1423–1427 (1996).

123 Cruts, M. et al. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442, 920–924 (2006).

124 Baker, M. et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442, 916–919 (2006).

125 Mahadevan, M. et al. Myotonic dystrophy mutation: an unstable CTG repeat in the 3′ untranslated region of the gene. Science 255, 1253–1255 (1992).

126 Liquori, C. L. et al. Myotonic dystrophy type 2 caused by a CCTG expansion in intron 1 of ZNF9. Science 293, 864–867 (2001).

127 Brook, J. D. et al. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member. Cell 69, 385 (1992).

128 Mankodi, A. et al. Expanded CUG repeats trigger aberrant splicing of ClC-1 chloride channel pre-mRNA and hyperexcitability of skeletal muscle in myotonic dystrophy. Mol. Cell 10, 35–44 (2002).

129 Philips, A. V., Timchenko, L. T. & Cooper, T. A. Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy. Science 280, 737–741 (1998).

130 Sergeant, N. et al. Dysregulation of human brain microtubule-associated tau mRNA maturation in myotonic dystrophy type 1. Hum. Mol. Genet. 10, 2143–2155 (2001).

131 Miller, J. W. et al. Recruitment of human muscleblind proteins to (CUG)(n) expansions associated with myotonic dystrophy. EMBO J. 19, 4439–4448 (2000).

132 Suenaga, K. et al. Muscleblind-like 1 knockout mice reveal novel splicing defects in the myotonic dystrophy brain. PLoS ONE 7, e33218 (2012).

133 Kanadia, R. N. et al. A muscleblind knockout model for myotonic dystrophy. Science 302, 1978–1980 (2003).

134 Fratta, P. et al. C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes. Sci. Rep. 2, 1016 (2012).

135 Pearson, C. E. Repeat associated non-ATG translation initiation: one DNA, two transcripts, seven reading frames, potentially nine toxic entities! PLoS Genet 7, e1002018 (2011).

136 Zu, T. et al. Non-ATG-initiated translation directed by microsatellite expansions. Proc. Natl Acad. Sci. USA 108, 260–265 (2011).

137 Mori, K. et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 7 Feb 2013 (doi:10.1126/science.1232927).

138 Ash, P. E. et al. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 77, 639–646 (2013).

139 Takahashi, H. et al. Widespread multiple system degeneration in a patient with familial amyotrophic lateral sclerosis. J. Neurol. Sci. 120, 15–21 (1993).

140 Kanning, K. C., Kaplan, A. & Henderson, C. E. Motor neuron diversity in development and disease. Annu. Rev. Neurosci. 33, 409–440 (2010).

141 Pun, S. et al. Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF. Nature Neurosci. 9, 408–419 (2006).

142 Van Hoecke, A. et al. EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans. Nature Med. 18, 1418–1422 (2012). Using a zebrafish screening model for ALS, these authors identified EPHA4 as a major disease modifier, a finding that was confirmed in several different models of motor neuron disease. Interestingly, these authors found that EPHA4 expression levels in patients with ALS are irreversibly correlated with disease onset and survival.

143 Corona, J. C., Tovar- y-Romo, L. B. & Tapia, R. Glutamate excitotoxicity and therapeutic targets for amyotrophic lateral sclerosis. Expert Opin. Ther. Targets 11, 1415–1428 (2007).

144 Rothstein, J. D., Martin, L. J. & Kuncl, R. W. Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N. Engl. J. Med. 326, 1464–1468 (1992).

145 Bruijn, L. I. et al. ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 18, 327–338 (1997).

146 Mitchell, J. et al. Familial amyotrophic lateral sclerosis is associated with a mutation in D-amino acid oxidase. Proc. Natl Acad. Sci. USA 107, 7556–7561 (2010).

147 Fossat, P. et al. Glial D-serine gates NMDA receptors at excitatory synapses in prefrontal cortex. Cereb. Cortex 22, 595–606 (2012).

148 Lobsiger, C. S., Boillee, S. & Cleveland, D. W. Toxicity from different SOD1 mutants dysregulates the complement system and the neuronal regenerative response in ALS motor neurons. Proc. Natl Acad. Sci. USA 104, 7319–7326 (2007).

149 Mishina, M. et al. A single amino acid residue determines the Ca2+ permeability of AMPA-selective glutamate receptor channels. Biochem. Biophys. Res. Commun. 180, 813–821 (1991).

150 Van Damme, P. et al. Astrocytes regulate GluR2 expression in motor neurons and their vulnerability to excitotoxicity. Proc. Natl Acad. Sci. USA 104, 14825–14830 (2007).

151 Vanselow, B. K. & Keller, B. U. Calcium dynamics and buffering in oculomotor neurones from mouse that are particularly resistant during amyotrophic lateral sclerosis (ALS)-related motoneurone disease. J. Physiol. 525, 433–445 (2000).

152 Yamanaka, K. et al. Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nature Neurosci. 11, 251–253 (2008).

153 Boillee, S., Vande Velde, C. & Cleveland, D. W. ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron 52, 39–59 (2006).

154 Boillee, S. et al. Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312, 1389–1392 (2006). This is the first paper to evaluate the individual contribution of different cell types to the phenotype of the SOD1G37R mouse model and supports the idea that glial cells contribute to motor neuron disease.

155 Wang, L., Gutmann, D. H. & Roos, R. P. Astrocyte loss of mutant SOD1 delays ALS disease onset and progression in G85R transgenic mice. Hum. Mol. Genet. 20, 286–293 (2011).

156 Wang, L. et al. The effect of mutant SOD1 dismutase activity on non-cell autonomous degeneration in familial amyotrophic lateral sclerosis. Neurobiol. Dis. 35, 234–240 (2009).

157 Haidet-Phillips, A. M. et al. Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. Nature Biotech. 29, 824–828 (2011). The authors found that astrocytes derived from patients with SALS are toxic to co-cultured motor neurons through a SOD1-related mechanism, supporting the idea that wild-type SOD1s can contribute to SALS.

158 Appel, S. H. et al. The microglial–motoneuron dialogue in ALS. Acta Myol. 30, 4–8 (2011).

159 Butovsky, O. et al. Modulating inflammatory monocytes with a unique microRNA gene signature ameliorates murine ALS. J. Clin. Invest. 122, 3063–3087 (2012).

160 Beers, D. R. et al. CD4+ T cells support glial neuroprotection, slow disease progression, and modify glial morphology in an animal model of inherited ALS. Proc. Natl Acad. Sci. USA 105, 15558–15563 (2008).

161 Chiu, I. M. et al. T lymphocytes potentiate endogenous neuroprotective inflammation in a mouse model of ALS. Proc. Natl Acad. Sci. USA 105, 17913–17918 (2008).

162 Engelhardt, J. I., Tajti, J. & Appel, S. H. Lymphocytic infiltrates in the spinal cord in amyotrophic lateral sclerosis. Arch. Neurol. 50, 30–36 (1993).

163 Beers, D. R. et al. Endogenous regulatory T lymphocytes ameliorate amyotrophic lateral sclerosis in mice and correlate with disease progression in patients with amyotrophic lateral sclerosis. Brain 134, 1293–1314 (2011).

164 Henkel, J. S. et al. Regulatory T-lymphocytes mediate amyotrophic lateral sclerosis progression and survival. EMBO Mol. Med. 5, 64–79 (2012).

165 Lee, Y. et al. Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 487, 443–448 (2012). This is the first paper to indicate that oligodendrocytes mediate metabolic support to neurons through their expression of MCT1 monocarboxylate transporters, which provide neurons with the metabolite lactate. As a lack of this transporter leads to motor neuron degeneration, the reduction in MCT1 expression found in patients with ALS and in ALS mouse models probably contributes to motor neuron disease.

166 Philips, T. et al. Oligodendrocyte dysfunction in the pathogenesis of amyotrophic lateral sclerosis. Brain 136, 471–482 (2013)

167 Miller, T. M. et al. 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 (2006).

168 Williams, A. H. et al. MicroRNA-206 delays ALS progression and promotes regeneration of neuromuscular synapses in mice. Science 326, 1549–1554 (2009).

169 Zhong, Z. et al. Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells. J. Clin. Invest. 119, 3437–3449 (2009).

170 Zhong, Z. et al. ALS-causing SOD1 mutants generate vascular changes prior to motor neuron degeneration. Nature Neurosci. 11, 420–422 (2008).

171 Yamanaka, K. et al. Mutant SOD1 in cell types other than motor neurons and oligodendrocytes accelerates onset of disease in ALS mice. Proc. Natl Acad. Sci. USA 105, 7594–7599 (2008).

172 Schmidt, E. R., Pasterkamp, R. J. & van den Berg, L. H. Axon guidance proteins: novel therapeutic targets for ALS? Prog. Neurobiol. 88, 286–301 (2009).

173 Bergeron, C. et al. Neurofilament light and polyadenylated mRNA levels are decreased in amyotrophic lateral sclerosis motor neurons. J. Neuropathol. Exp. Neurol. 53, 221–230 (1994).

174 Strong, M. J. et al. TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein. Mol. Cell Neurosci. 35, 320–327 (2007).

175 Volkening, K. et al. Tar DNA binding protein of 43 kDa (TDP-43), 14-3-3 proteins and copper/zinc superoxide dismutase (SOD1) interact to modulate NFL mRNA stability. Implications for altered RNA processing in amyotrophic lateral sclerosis (ALS). Brain Res. 1305, 168–182 (2009).

176 Gros-Louis, F. et al. A frameshift deletion in peripherin gene associated with amyotrophic lateral sclerosis. J. Biol. Chem. 279, 45951–45956 (2004).

177 Figlewicz, D. A. et al. Variants of the heavy neurofilament subunit are associated with the development of amyotrophic lateral sclerosis. Hum. Mol. Genet. 3, 1757–1761 (1994).

178 Tomkins, J. et al. Novel insertion in the KSP region of the neurofilament heavy gene in amyotrophic lateral sclerosis (ALS). Neuroreport 9, 3967–3970 (1998).

179 Puls, I. et al. Mutant dynactin in motor neuron disease. Nature Genet. 33, 455–456 (2003).

180 Munch, C. et al. Point mutations of the p150 subunit of dynactin (DCTN1) gene in ALS. Neurology 63, 724–726 (2004).

181 Wu, C. H. et al. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 488, 499–503 (2012). Together with EPHA4, PFN1 is one of the recently identified genes associated with axonal outgrowth that are involved in motor neuron disease. These genes provide strong support for continuing the assessment of cytoskeletal disorganization and axonal transport impairment as important disease-causing mechanisms.

182 Winning, R. S. et al. EphA4 catalytic activity causes inhibition of RhoA GTPase in Xenopus laevis embryos. Differentiation 70, 46–55 (2002).

183 Tsuda, H. et al. The amyotrophic lateral sclerosis 8 protein VAPB is cleaved, secreted, and acts as a ligand for Eph receptors. Cell 133, 963–977 (2008).

184 Nishimura, A. L. et al. A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am. J. Hum. Genet. 75, 822–831 (2004).

185 Yang, Y. et al. The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nature Genet. 29, 160–165 (2001).

186 Linseman, D. A. & Loucks, F. A. Diverse roles of Rho family GTPases in neuronal development, survival, and death. Front. Biosci. 13, 657–676 (2008).

187 Dupuis, L. et al. Nogo provides a molecular marker for diagnosis of amyotrophic lateral sclerosis. Neurobiol. Dis. 10, 358–365 (2002).

188 Jokic, N. et al. The neurite outgrowth inhibitor Nogo-A promotes denervation in an amyotrophic lateral sclerosis model. EMBO Rep. 7, 1162–1167 (2006).

189 Ruiz de Almodovar, C. et al. VEGF mediates commissural axon chemoattraction through its receptor Flk1. Neuron 70, 966–978 (2011).

190 Carmeliet, P. et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380, 435–439 (1996).

191 Storkebaum, E. et al. Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS. Nature Neurosci. 8, 85–92 (2005).

192 Landers, J. E. et al. Reduced expression of the Kinesin-Associated Protein 3 (KIFAP3) gene increases survival in sporadic amyotrophic lateral sclerosis. Proc. Natl Acad. Sci. USA 106, 9004–9009 (2009).

193 Traynor, B. J. et al. Kinesin-associated protein 3 (KIFAP3) has no effect on survival in a population-based cohort of ALS patients. Proc. Natl Acad. Sci. USA 107, 12335–12338 (2010).

194 van Es, M. A. et al. Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nature Genet. 41, 1083–1087 (2009).

195 Diekstra, F. P. et al. UNC13A is a modifier of survival in amyotrophic lateral sclerosis. Neurobiol. Aging 33, 630.e3–630.e8 (2012).

196 Simpson, C. L. et al. Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration. Hum. Mol. Genet. 18, 472–481 (2009).

197 Klassen, R. et al. DNA repair defects sensitize cells to anticodon nuclease yeast killer toxins. Mol. Genet. Genom. 285, 185–195 (2011).

198 Miskiewicz, K. et al. ELP3 controls active zone morphology by acetylating the ELKS family member Bruchpilot. Neuron 72, 776–788 (2011).

199 Mackenzie, I. R., Rademakers, R. & Neumann, M. TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol. 9, 995–1007 (2010).

200 Lillo, P. & Hodges, J. R. Frontotemporal dementia and motor neurone disease: overlapping clinic-pathological disorders. J. Clin. Neurosci. 16, 1131–1135 (2009).

201 Mackenzie, I. R. et al. Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann. Neurol. 61, 427–434 (2007).

202 Burrell, J. R. et al. Motor neuron dysfunction in frontotemporal dementia. Brain 134, 2582–2594 (2011).

203 Lomen-Hoerth, C., Anderson, T. & Miller, B. The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology 59, 1077–1079 (2002).

204 Turner, B. J. & Talbot, K. Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS. Prog. Neurobiol. 85, 94–134 (2008).

205 Feiguin, F. et al. Depletion of TDP-43 affects Drosophila motoneurons terminal synapsis and locomotive behavior. FEBS Lett. 583, 1586–1592 (2009).

206 Laird, A. S. et al. Progranulin is neurotrophic in vivo and protects against a mutant TDP-43 induced axonopathy. PLoS ONE 5, e13368 (2010).

207 Kraemer, B. C. et al. Loss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis. Acta Neuropathol. 119, 409–419 (2010).

208 Wu, L. S., Cheng, W. C. & Shen, C. K. Targeted depletion of TDP-43 expression in the spinal cord motor neurons leads to the development of amyotrophic lateral sclerosis-like phenotypes in mice. J. Biol. Chem. 287, 27335–27344 (2012).

209 Liachko, N. F., Guthrie, C. R. & Kraemer, B. C. Phosphorylation promotes neurotoxicity in a Caenorhabditis elegans model of TDP-43 proteinopathy. J. Neurosci. 30, 16208–16219 (2010).

210 Da Cruz, S. & Cleveland, D. W. Understanding the role of TDP-43 and FUS/TLS in ALS and beyond. Curr. Opin. Neurobiol. 21, 904–919 (2011).

211 Stallings, N. R. et al. Progressive motor weakness in transgenic mice expressing human TDP-43. Neurobiol. Dis. 40, 404–414 (2010).

212 Wegorzewska, I. et al. TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration. Proc. Natl Acad. Sci. USA 106, 18809–18814 (2009).

213 Wils, H. et al. TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration. Proc. Natl Acad. Sci. USA 107, 3858–3863 (2010).

214 Zhou, H. et al. Transgenic rat model of neurodegeneration caused by mutation in the TDP gene. PLoS Genet. 6, e1000887 (2010).

215 Uchida, A. et al. Non-human primate model of amyotrophic lateral sclerosis with cytoplasmic mislocalization of TDP-43. Brain 135, 833–846 (2012).

216 Huang, C. et al. Mutant TDP-43 in motor neurons promotes the onset and progression of ALS in rats. J. Clin. Invest. 122, 107–118 (2012).

217 Hicks, G. G. et al. Fus deficiency in mice results in defective B-lymphocyte development and activation, high levels of chromosomal instability and perinatal death. Nature Genet. 24, 175–179 (2000).

218 Kuroda, M. et al. Male sterility and enhanced radiation sensitivity in TLS−/− mice. EMBO J. 19, 453–462 (2000).

219 Fujii, R. et al. The RNA binding protein TLS is translocated to dendritic spines by mGluR5 activation and regulates spine morphology. Curr. Biol. 15, 587–593 (2005).

220 Huang, C. et al. FUS transgenic rats develop the phenotypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. PLoS Genet. 7, e1002011 (2011).

221 Mitchell, J. C. et al. Overexpression of human wild-type FUS causes progressive motor neuron degeneration in an age- and dose-dependent fashion. Acta Neuropathol. 125, 273–288 (2013).

222 Smith, R. A. et al. Antisense oligonucleotide therapy for neurodegenerative disease. J. Clin. Invest. 116, 2290–2296 (2006).

223 Gros-Louis, F. et al. Intracerebroventricular infusion of monoclonal antibody or its derived Fab fragment against misfolded forms of SOD1 mutant delays mortality in a mouse model of ALS. J. Neurochem. 113, 1188–1199 (2010).

224 Wheeler, T. M. et al. Targeting nuclear RNA for in vivo correction of myotonic dystrophy. Nature 488, 111–115 (2012).

225 Moreno-Igoa, M. et al. Fragment C of tetanus toxin, more than a carrier. Novel perspectives in non-viral ALS gene therapy. J. Mol. Med. 88, 297–308 (2010).

226 Foust, K. D. et al. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nature Biotech. 27, 59–65 (2009).

227 Gowing, G. & Svendsen, C. N. Stem cell transplantation for motor neuron disease: current approaches and future perspectives. Neurotherapeutics 8, 591–606 (2011).

228 Dimos, J. T. et al. Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321, 1218–1221 (2008). This is the first paper to describe the generation of motor neurons from fibroblasts from an elderly patient with FALS. Fibroblasts from a patient with ALS were reprogrammed into a pluripotent state and subsequently differentiated into motor neurons, which could then be used for a whole range of new therapeutic applications.

229 Glass, J. D. et al. Lumbar intraspinal injection of neural stem cells in patients with amyotrophic lateral sclerosis: results of a phase I trial in 12 patients. Stem Cells 30, 1144–1151 (2012).

230 Lepore, A. C. et al. Focal transplantation-based astrocyte replacement is neuroprotective in a model of motor neuron disease. Nature Neurosci. 11, 1294–1301 (2008).

231 Rosen, D. R. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 364, 59–62 (1993).

232 Greenway, M. J. et al. ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis. Nature Genet. 38, 411–413 (2006).

233 Chen, Y. Z. et al. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am. J. Hum. Genet. 74, 1128–1135 (2004).

234 Orlacchio, A. et al. SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis. Brain 133, 591–598 (2010).

235 Hadano, S. et al. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nature Genet. 29, 166–173 (2001).

236 Hand, C. K. et al. A novel locus for familial amyotrophic lateral sclerosis, on chromosome 18q. Am. J. Hum. Genet. 70, 251–256 (2002).

237 Sapp, P. C. et al. Identification of two novel loci for dominantly inherited familial amyotrophic lateral sclerosis. Am. J. Hum. Genet. 73, 397–403 (2003).