Decoding ALS: From genes to mechanism

Nature

Volumn 539, Issue 7628, 2016, Pages 197-206

  Taylor, J Paul ^a   Brown, Robert H ^b   Cleveland, Don W ^c,d  

^a ST JUDE CHILDREN S RESEARCH HOSPITAL   (United States)

^b UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL   (United States)

^c UNIVERSITY OF CALIFORNIA   (United States)

^d UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DIPEPTIDE; RIBONUCLEOPROTEIN; RNA; C9ORF72 PROTEIN, HUMAN; PRION; PROTEIN;

HOMEOSTASIS; METABOLISM; NERVOUS SYSTEM DISORDER; NEUROLOGY; PHASE TRANSITION; PROTEIN; RNA;

AMYOTROPHIC LATERAL SCLEROSIS; AXONAL INJURY; BIOGENESIS; CELL MIGRATION; CELL ORGANELLE; CYTOPLASM; DEGENERATIVE DISEASE; DISEASE COURSE; DYNAMICS; ENDOPLASMIC RETICULUM; ENDOPLASMIC RETICULUM STRESS; GENE; GLIA; HEREDITY; HUMAN; MOTONEURON; NONHUMAN; PHASE SEPARATION; PRION; PRIORITY JOURNAL; PROTEIN DEGRADATION; PROTEIN HOMEOSTASIS; REVIEW; RNA METABOLISM; STRESS; ANIMAL; BIOSYNTHESIS; FRONTOTEMPORAL DEMENTIA; GENETICS; METABOLISM; NERVOUS SYSTEM; PATHOLOGY; PATHOPHYSIOLOGY; TRANSPORT AT THE CELLULAR LEVEL;

AMYOTROPHIC LATERAL SCLEROSIS; ANIMALS; BIOLOGICAL TRANSPORT; ENDOPLASMIC RETICULUM STRESS; FRONTOTEMPORAL DEMENTIA; HUMANS; NERVOUS SYSTEM; ORGANELLES; PRIONS; PROTEINS; PROTEOLYSIS; RNA;

EID: 85012041135     PISSN: 00280836     EISSN: 14764687     Source Type: Journal    
DOI: 10.1038/nature20413     Document Type: Review

References (147)

1. Al-Chalabi, A. & Hardiman, O. The epidemiology of ALS: A conspiracy of genes, environment and time. Nature Rev. Neurol. 9, 617-628 (2013).
2. Rosen, D. R. et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362, 59-62 (1993).
3. Gamez, J. et al. Mutational analysis of the Cu/Zn superoxide dismutase gene in a Catalan ALS population: should all sporadic ALS cases also be screened for SOD1? J. Neurol. Sci. 247, 21-28 (2006).
4. Cooper-Knock, J. et al. Clinico-pathological features in amyotrophic lateral sclerosis with expansions in C9ORF72. Brain 135, 751-764 (2012).
5. Elden, A. C. et al. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466, 1069-1075 (2010).
6. 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).
7. Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130-133 (2006).
8. 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).
9. Al-Sarraj, S. et al. p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS. Acta Neuropathol. 122, 691-702 (2011).
10. Gurney, M. E. et al. Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science 264, 1772-1775 (1994).
11. Wong, P. C. et al. An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron 14, 1105-1116 (1995).
12. Bruijn, L. I. et al. Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-Type SOD1. Science 281, 1851-1854 (1998).
13. Cleveland, D. W., Laing, N., Hurse, P. V. & Brown, R. H. Jr. Toxic mutants in Charcot's sclerosis. Nature 378, 342-343 (1995).
14. 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).
15. Parone, P. A. et al. Enhancing mitochondrial calcium buffering capacity reduces aggregation of misfolded SOD1 and motor neuron cell death without extending survival in mouse models of inherited amyotrophic lateral sclerosis. J. Neurosci. 33, 4657-4671 (2013).
16. 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).
17. Ralph, G. S. et al. Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model. Nature Med. 11, 429-433 (2005).
18. Yamanaka, K. et al. Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nature Neurosci. 11, 251-253 (2008).
19. Boillee, S. et al. Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312, 1389-1392 (2006).
20. Beers, D. R. et al. Wild-Type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc. Natl Acad. Sci. USA 103, 16021- 16026 (2006).
21. Frakes, A. E. et al. Microglia induce motor neuron death via the classical NF-κB pathway in amyotrophic lateral sclerosis. Neuron 81, 1009-1023 (2014).
22. Harraz, M. M. et al. SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model. J. Clin. Invest. 118, 659-670 (2008).
23. O'Rourke, J. G. et al. C9orf72 is required for proper macrophage and microglial function in mice. Science 351, 1324-1329 (2016).
24. Jiang, J. et al. Gain of toxicity from ALS/FTD-linked repeat expansions in C9ORF72 is alleviated by antisense oligonucleotides targeting GGGGCCcontaining RNAs. Neuron 90, 535-550 (2016).
25. Burberry, A. et al. Loss-of-function mutations in the C9ORF72 mouse ortholog cause fatal autoimmune disease. Sci. Transl. Med. 8, 347-93 (2016).
26. Kang, S. H. et al. Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis. Nature Neurosci. 16, 571-579 (2013).
27. Lee, Y. et al. Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 487, 443-448 (2012).
28. 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).
29. Howland, D. S. et al. Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proc. Natl Acad. Sci. USA 99, 1604-1609 (2002).
30. Rothstein, J. D., Van Kammen, M., Levey, A. I., Martin, L. J. & Kuncl, R. W. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann. Neurol. 38, 73-84 (1995).
31. 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).
32. Di Giorgio, F. P., Carrasco, M. A., Siao, M. C., Maniatis, T. & Eggan, K. Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nature Neurosci. 10, 608-614 (2007).
33. Marchetto, M. C. et al. Non-cell-Autonomous effect of human SOD1G37R astrocytes on motor neurons derived from human embryonic stem cells. Cell Stem Cell 3, 649-657 (2008).
34. Nagai, M. et al. Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nature Neurosci. 10, 615-622 (2007).
35. Haidet-Phillips, A. M. et al. Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. Nature Biotechnol. 29, 824-828 (2011).
36. Re, D. B. et al. Necroptosis drives motor neuron death in models of both sporadic and familial ALS. Neuron 81, 1001-1008 (2014).
37. 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).
38. Nishitoh, H. et al. ALS-linked mutant SOD1 induces ER stress-And ASK1- dependent motor neuron death by targeting Derlin-1. Genes Dev. 22, 1451- 1464 (2008).
39. Saxena, S., Cabuy, E. & Caroni, P. A role for motoneuron subtype-selective ER stress in disease manifestations of FALS mice. Nature Neurosci. 12, 627-636 (2009).
40. 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).
41. Fecto, F. et al. SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch. Neurol. 68, 1440-1446 (2011).
42. Maruyama, H. et al. Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465, 223-226 (2010).
43. Wild, P. et al. Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 333, 228-233 (2011).
44. Johnson, J. O. et al. Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68, 857-864 (2010).
45. Parkinson, N. et al. ALS phenotypes with mutations in CHMP2B (charged multivesicular body protein 2B). Neurology 67, 1074-1077 (2006).
46. Chen, H. J. et al. Characterization of the properties of a novel mutation in VAPB in familial amyotrophic lateral sclerosis. J. Biol. Chem. 285, 40266-40281 (2010).
47. Kabashi, E., Agar, J. N., Taylor, D. M., Minotti, S. & Durham, H. D. Focal dysfunction of the proteasome: A pathogenic factor in a mouse model of amyotrophic lateral sclerosis. J. Neurochem. 89, 1325-1335 (2004).
48. Urushitani, M., Kurisu, J., Tsukita, K. & Takahashi, R. Proteasomal inhibition by misfolded mutant superoxide dismutase 1 induces selective motor neuron death in familial amyotrophic lateral sclerosis. J. Neurochem. 83, 1030-1042 (2002).
49. 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).
50. Chen, X. J. et al. Proprioceptive sensory neuropathy in mice with a mutation in the cytoplasmic dynein heavy chain 1 gene. J. Neurosci. 27, 14515-14524, (2007).
51. Perlson, E. et al. A switch in retrograde signaling from survival to stress in rapidonset neurodegeneration. J. Neurosci. 29, 9903-9917 (2009).
52. Puls, I. et al. Mutant dynactin in motor neuron disease. Nature Genet. 33, 455-456 (2003).
53. Gill, S. R. et al. Dynactin, a conserved, ubiquitously expressed component of an activator of vesicle motility mediated by cytoplasmic dynein. J. Cell Biol. 115, 1639-1650 (1991).
54. Sutton, M. A. & Schuman, E. M. Dendritic protein synthesis, synaptic plasticity, and memory. Cell 127, 49-58 (2006).
55. Alami, N. H. et al. Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations. Neuron 81, 536-543 (2014).
56. Jucker, M. & Walker, L. C. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501, 45-51 (2013).
57. Grad, L. I. et al. Intermolecular transmission of superoxide dismutase 1 misfolding in living cells. Proc. Natl Acad. Sci. USA 108, 16398-16403 (2011).
58. Münch, 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).
59. Deng, H. X. et al. Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria. Proc. Natl Acad. Sci. USA 103, 7142-7147 (2006).
60. Ayers, J. I., Fromholt, S. E., O'Neal, V. M., Diamond, J. H. & Borchelt, D. R. Prionlike propagation of mutant SOD1 misfolding and motor neuron disease spread along neuroanatomical pathways. Acta Neuropathol. 131, 103-114 (2016).
61. Ravits, J. M. & La Spada, A. R. ALS motor phenotype heterogeneity, focality, and spread: deconstructing motor neuron degeneration. Neurology 73, 805-811 (2009).
62. Urushitani, M. et al. Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis. Nature Neurosci. 9, 108-118 (2006).
63. Lee, J. G., Takahama, S., Zhang, G., Tomarev, S. I. & Ye, Y. Unconventional secretion of misfolded proteins promotes adaptation to proteasome dysfunction in mammalian cells. Nature Cell Biol. 18, 765-776 (2016).
64. Salajegheh, M. et al. Sarcoplasmic redistribution of nuclear TDP-43 in inclusion body myositis. Muscle Nerve 40, 19-31 (2009).
65. Lippa, C. F. et al. Transactive response DNA-binding protein 43 burden in familial Alzheimer disease and Down syndrome. Arch. Neurol. 66, 1483-1488 (2009).
66. Chanson, J. B. et al. TDP43-positive intraneuronal inclusions in a patient with motor neuron disease and Parkinson's disease. Neurodegener. Dis. 7, 260-264 (2010).
67. Sreedharan, J. et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319, 1668-1672 (2008).
68. Vance, C. et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323, 1208-1211 (2009).
69. 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).
70. Kim, H. J. et al. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495, 467-473 (2013).
71. Liu, Q. et al. Whole-exome sequencing identifies a missense mutation in hnRNPA1 in a family with flail arm ALS. Neurology http://dx.doi.org/10.1212/WNL.0000000000003256 (2016).
72. Tollervey, J. R. et al. Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nature Neurosci. 14, 452-458 (2011).
73. 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).
74. 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).
75. Huelga, S. C. et al. Integrative genome-wide analysis reveals cooperative regulation of alternative splicing by hnRNP proteins. Cell Rep. 1, 167-178 (2012).
76. Johnson, J. O. et al. Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis. Nature Neurosci. 17, 664-666 (2014).
77. 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).
78. Hyman, A. A., Weber, C. A. & Julicher, F. Liquid-liquid phase separation in biology. Annu. Rev. Cell Dev. Biol. 30, 39-58 (2014).
79. Molliex, A. et al. Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization. Cell 163, 123-133 (2015).
80. Patel, A. et al. A liquid-To-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell 162, 1066-1077 (2015).
81. Lin, Y., Protter, D. S., Rosen, M. K. & Parker, R. Formation and maturation of phase-separated liquid droplets by RNA-binding proteins. Mol. Cell 60, 208-219 (2015).
82. Lagier-Tourenne, C., Polymenidou, M. & Cleveland, D. W. TDP-43 and FUS/TLS: Emerging roles in RNA processing and neurodegeneration. Hum. Mol. Genet. 19, R46-R64 (2010).
83. Shang, Y. & Huang, E. J. Mechanisms of FUS mutations in familial amyotrophic lateral sclerosis. Brain Res. 1647, 65-78 (2016).
84. Murakami, T. et al. ALS/FTD mutation-induced phase transition of FUS liquid droplets and reversible hydrogels into irreversible hydrogels impairs RNP granule function. Neuron 88, 678-690 (2015).
85. Lim, S. M. et al. Directly converted patient-specific induced neurons mirror the neuropathology of FUS with disrupted nuclear localization in amyotrophic lateral sclerosis. Mol. Neurodegener. 11, 8 (2016).
86. Ramaswami, M., Taylor, J. P. & Parker, R. Altered ribostasis: RNA-protein granules in degenerative disorders. Cell 154, 727-736 (2013).
87. Buratti, E. & Baralle, F. E. The molecular links between TDP-43 dysfunction and neurodegeneration. Adv. Genet. 66, 1-34 (2009).
88. Ling, J. P., Pletnikova, O., Troncoso, J. C. & Wong, P. C. TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD. Science 349, 650-655 (2015).
89. Zhang, Z. et al. Downregulation of microRNA-9 in iPSC-derived neurons of FTD/ALS patients with TDP-43 mutations. PLoS ONE 8, e76055 (2013).
90. Valdez, G., Heyer, M. P., Feng, G. & Sanes, J. R. The role of muscle microRNAs in repairing the neuromuscular junction. PLoS ONE 9, e93140 (2014).
91. Williams, A. H. et al. MicroRNA-206 delays ALS progression and promotes regeneration of neuromuscular synapses in mice. Science 326, 1549-1554 (2009).
92. Emde, A. et al. Dysregulated miRNA biogenesis downstream of cellular stress and ALS-causing mutations: A new mechanism for ALS. EMBO J. 34, 2633-2651 (2015).
93. Cloutier, F., Marrero, A., O'Connell, C. & Morin, P. Jr. MicroRNAs as potential circulating biomarkers for amyotrophic lateral sclerosis. J. Mol. Neurosci. 56, 102-112 (2015).
94. Morita, M. et al. A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology 66, 839-844 (2006).
95. Vance, C. et al. Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2-21.3. Brain 129, 868-876 (2006).
96. Shatunov, A. et al. Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: A genome-wide association study. Lancet Neurol. 9, 986-994 (2010).
97. Laaksovirta, H. et al. Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: A genome-wide association study. Lancet Neurol. 9, 978-985 (2010).
98. Van Deerlin, V. M. et al. Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nature Genet. 42, 234-239 (2010).
99. 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).
100. Waite, A. J. et al. Reduced C9orf72 protein levels in frontal cortex of amyotrophic lateral sclerosis and frontotemporal degeneration brain with the C9ORF72 hexanucleotide repeat expansion. Neurobiol. Aging 35, 1779.e5-e13 (2014).
101. Webster, C. P. et al. The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy. EMBO J. 35, 1656-1676 (2016).
102. Sellier, C. et al. Loss of C9ORF72 impairs autophagy and synergizes with polyQ Ataxin-2 to induce motor neuron dysfunction and cell death. EMBO J. 35, 1276-1297 (2016).
103. Lagier-Tourenne, C. et al. Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration. Proc. Natl Acad. Sci. USA 110, E4530-E4539 (2013).
104. Koppers, M. et al. C9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits. Ann. Neurol. 78, 426-438 (2015).
105. Atanasio, A. et al. C9orf72 ablation causes immune dysregulation characterized by leukocyte expansion, autoantibody production, and glomerulonephropathy in mice. Sci. Rep. 6, 23204 (2016).
106. Chew, J. et al. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits. Science 348, 1151-1154 (2015).
107. Gendron, T. F. et al. Antisense transcripts of the expanded C9ORF72 hexanucleotide repeat form nuclear RNA foci and undergo repeat-Associated non-ATG translation in c9FTD/ALS. Acta Neuropathol. 126, 829-844 (2013).
108. Mori, K. et al. Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins. Acta Neuropathol. 126, 881-893 (2013).
109. Zu, T. et al. RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proc. Natl Acad. Sci. USA 110, E4968-E4977 (2013).
110. La Spada, A. R. & Taylor, J. P. Repeat expansion disease: progress and puzzles in disease pathogenesis. Nature Rev. Genet. 11, 247-258 (2010).
111. Haeusler, A. R. et al. C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature 507, 195-200 (2014).
112. Lee, Y. B. et al. Hexanucleotide repeats in ALS/FTD form length-dependent RNA foci, sequester RNA binding proteins, and are neurotoxic. Cell Rep. 5, 1178- 1186 (2013).
113. Mackenzie, I. R. et al. Dipeptide repeat protein pathology in C9ORF72 mutation cases: clinico-pathological correlations. Acta Neuropathol. 126, 859-879 (2013).
114. Xu, Z. et al. Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration. Proc. Natl Acad. Sci. USA 110, 7778-7783 (2013).
115. Cooper-Knock, J. et al. Antisense RNA foci in the motor neurons of C9ORF72- ALS patients are associated with TDP-43 proteinopathy. Acta Neuropathol. 130, 63-75 (2015).
116. Zhang, K. et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525, 56-61 (2015).
117. Taylor, J. P. Neurodegenerative diseases: G-quadruplex poses quadruple threat. Nature 507, 175-177 (2014).
118. Burguete, A. S. et al. GGGGCC microsatellite RNA is neuritically localized, induces branching defects, and perturbs transport granule function. eLife 4, e08881 (2015).
119. Ishiguro, A., Kimura, N., Watanabe, Y., Watanabe, S. & Ishihama, A. TDP-43 binds and transports G-quadruplex-containing mRNAs into neurites for local translation. Genes Cells 21, 466-481 (2016).
120. Zu, T. et al. Non-ATG-initiated translation directed by microsatellite expansions. Proc. Natl Acad. Sci. USA 108, 260-265 (2011).
121. Ash, P. E. et al. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 77, 639-646 (2013).
122. Mori, K. et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339, 1335-1338 (2013).
123. Mackenzie, I. R. et al. Quantitative analysis and clinico-pathological correlations of different dipeptide repeat protein pathologies in C9ORF72 mutation carriers. Acta Neuropathol. 130, 845-861 (2015).
124. Schludi, M. H. et al. Distribution of dipeptide repeat proteins in cellular models and C9orf72 mutation cases suggests link to transcriptional silencing. Acta Neuropathol. 130, 537-555 (2015).
125. Kwon, I. et al. Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells. Science 345, 1139-1145 (2014).
126. Mizielinska, S. et al. C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science 345, 1192-1194 (2014).
127. Wen, X. et al. Antisense proline-Arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death. Neuron 84, 1213-1225 (2014).
128. Freibaum, B. D. et al. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature 525, 129-133 (2015).
129. Lee, K.-H. et al. C9orf72 dipeptide repeats impair the assembly, dynamics and function of membrane-less organelles. Cell 167, 774-788 (2016).
130. Lin, Y. et al. Toxic PR poly-dipeptides encoded by the C9orf72 repeat expansion target LC domain polymers. Cell 167, 789-802 (2016).
131. Yamakawa, M. et al. Characterization of the dipeptide repeat protein in the molecular pathogenesis of c9FTD/ALS. Hum. Mol. Genet. 24, 1630-1645 (2015).
132. Zhang, Y. J. et al. Aggregation-prone c9FTD/ALS poly(GA) RAN-Translated proteins cause neurotoxicity by inducing ER stress. Acta Neuropathol. 128, 505-524 (2014).
133. Zhang, Y. J. et al. C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins. Nature Neurosci. 19, 668-677 (2016).
134. Jovičić, A. et al. Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nature Neurosci. 18, 1226- 1229 (2015).
135. Donnelly, C. J. et al. RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron 80, 415-428 (2013).
136. Sareen, D. et al. Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion. Sci. Transl. Med. 5, 208-149 (2013).
137. O'Rourke, J. G. et al. C9orf72 BAC transgenic mice display typical pathologic features of ALS/FTD. Neuron 88, 892-901 (2015).
138. Peters, O. M. et al. Human C9ORF72 hexanucleotide expansion reproduces RNA foci and dipeptide repeat proteins but not neurodegeneration in BAC transgenic mice. Neuron 88, 902-909 (2015).
139. Liu, Y. et al. C9orf72 BAC mouse model with motor deficits and neurodegenerative features of ALS/FTD. Neuron 90, 521-534 (2016).
140. Brown, R. H. Jr. & Al-Chalabi, A. Endogenous retroviruses in ALS: A reawakening? Sci. Transl. Med. 7, 307-40 (2015).
141. Greenway, M. J. et al. ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis. Nature Genet. 38, 411-413 (2006).
142. Kabashi, E. et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nature Genet. 40, 572-574 (2008).
143. Teyssou, E. et al. Mutations in SQSTM1 encoding p62 in amyotrophic lateral sclerosis: genetics and neuropathology. Acta Neuropathol. 125, 511-522 (2013).
144. Wu, C. H. et al. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 488, 499-503 (2012).
145. Smith, B. N. et al. Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS. Neuron 84, 324-331 (2014).
146. Bannwarth, S. et al. A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement. Brain 137, 2329-2345 (2014).
147. Freischmidt, A. et al. Haploinsufficiency of TBK1 causes familial ALS and frontotemporal dementia. Nature Neurosci. 18, 631-636 (2015).