Journal of Neurology

, Volume 260, Issue 11, pp 2917–2927 | Cite as

Amyotrophic lateral sclerosis: an update on recent genetic insights

  • Yohei Iguchi
  • Masahisa Katsuno
  • Kensuke Ikenaka
  • Shinsuke Ishigaki
  • Gen SobueEmail author
Medical Progress in the Journal of Neurology


Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting both upper and lower motor neurons. The prognosis for ALS is extremely poor, but there is a limited course of treatment with only one approved medication. A most striking recent discovery is that TDP-43 is identified as a key molecule that is associated with both sporadic and familial forms of ALS. TDP-43 is not only a pathological hallmark, but also a genetic cause for ALS. Subsequently, a number of ALS-causative genes have been found. Above all, the RNA-binding protein, such as FUS, TAF15, EWSR1 and hnRNPA1, have structural and functional similarities to TDP-43, and physiological functions of some molecules, including VCP, UBQLN2, OPTN, FIG4 and SQSTM1, are involved in a protein degradation system. These discoveries provide valuable insight into the pathogenesis of ALS, and open doors for developing an effective disease-modifying therapy.


Amyotrophic lateral sclerosis Motor neuron disease Protein aggregation RNA metabolism 



This work was supported by Grant-in-Aids (KAKENHI) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Nos. 22110005, 21229011 and 23390230) and Core Research for Evolutional Science and Technology (CREST) from the Japan Science and Technology Agency (JST). Figure 3 was reproduced from Iguchi et al. Ref. [36].

Conflicts of interest



  1. 1.
    Arai T, Hasegawa M, Akiyama H et al (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351:602–611PubMedGoogle Scholar
  2. 2.
    Neumann M, Sampathu DM, Kwong LK et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133PubMedGoogle Scholar
  3. 3.
    Mackenzie IR, Neumann M, Cairns NJ et al (2011) Novel types of frontotemporal lobar degeneration: beyond tau and TDP-43. J Mol Neurosci 45:402–408PubMedGoogle Scholar
  4. 4.
    Gitcho MA, Baloh RH, Chakraverty S et al (2008) TDP-43 A315T mutation in familial motor neuron disease. Ann Neurol 63:535–538PubMedGoogle Scholar
  5. 5.
    Kabashi E, Valdmanis PN, Dion P et al (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 40:572–574PubMedGoogle Scholar
  6. 6.
    Sreedharan J, Blair IP, Tripathi VB et al (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319:1668–1672PubMedGoogle Scholar
  7. 7.
    Yokoseki A, Shiga A, Tan CF et al (2008) TDP-43 mutation in familial amyotrophic lateral sclerosis. Ann Neurol 63:538–542PubMedGoogle Scholar
  8. 8.
    Corcia P, Valdmanis P, Millecamps S et al (2012) Phenotype and genotype analysis in amyotrophic lateral sclerosis with TARDBP gene mutations. Neurology 78:1519–1526PubMedGoogle Scholar
  9. 9.
    Wang HY, Wang IF, Bose J et al (2004) Structural diversity and functional implications of the eukaryotic TDP gene family. Genomics 83:130–139PubMedGoogle Scholar
  10. 10.
    Ayala YM, Pantano S, D’Ambrogio A et al (2005) Human, Drosophila, and C. elegans TDP43: nucleic acid binding properties and splicing regulatory function. J Mol Biol 348:575–588PubMedGoogle Scholar
  11. 11.
    Buratti E, Brindisi A, Giombi M et al (2005) TDP-43 binds heterogeneous nuclear ribonucleoprotein A/B through its C-terminal tail: an important region for the inhibition of cystic fibrosis transmembrane conductance regulator exon 9 splicing. J Biol Chem 280:37572–37584PubMedGoogle Scholar
  12. 12.
    Strong MJ, Volkening K, Hammond R et al (2007) TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein. Mol Cell Neurosci 35:320–327PubMedGoogle Scholar
  13. 13.
    Buratti E, De Conti L, Stuani C et al (2010) Nuclear factor TDP-43 can affect selected microRNA levels. FEBS J 277:2268–2281PubMedGoogle Scholar
  14. 14.
    Polymenidou M, Lagier-Tourenne C, Hutt KR et al (2011) Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nat Neurosci 14:459–468PubMedGoogle Scholar
  15. 15.
    Tollervey JR, Curk T, Rogelj B et al (2011) Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat Neurosci 14:452–458PubMedGoogle Scholar
  16. 16.
    Sephton CF, Cenik C, Kucukural A et al (2011) Identification of neuronal RNA targets of TDP-43-containing ribonucleoprotein complexes. J Biol Chem 286:1204–1215PubMedGoogle Scholar
  17. 17.
    Xiao S, Sanelli T, Dib S et al (2011) RNA targets of TDP-43 identified by UV-CLIP are deregulated in ALS. Mol Cell Neurosci 47:167–180PubMedGoogle Scholar
  18. 18.
    Kawahara Y, Mieda-Sato A (2012) TDP-43 promotes microRNA biogenesis as a component of the Drosha and Dicer complexes. Proc Natl Acad Sci USA 109:3347–3352PubMedGoogle Scholar
  19. 19.
    Wegorzewska I, Bell S, Cairns NJ et al (2009) TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci USA 106:18809–18814PubMedGoogle Scholar
  20. 20.
    Wils H, Kleinberger G, Janssens J et al (2010) TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci USA 107:3858–3863PubMedGoogle Scholar
  21. 21.
    Xu YF, Gendron TF, Zhang YJ et al (2010) Wild-type human TDP-43 expression causes TDP-43 phosphorylation, mitochondrial aggregation, motor deficits, and early mortality in transgenic mice. J Neurosci 30:10851–10859PubMedGoogle Scholar
  22. 22.
    Stallings NR, Puttaparthi K, Luther CM et al (2010) Progressive motor weakness in transgenic mice expressing human TDP-43. Neurobiol Dis 40:404–414PubMedGoogle Scholar
  23. 23.
    Zhou H, Huang C, Chen H et al (2010) Transgenic rat model of neurodegeneration caused by mutation in the TDP gene. PLoS Genet 6:e1000887PubMedGoogle Scholar
  24. 24.
    Tsai KJ, Yang CH, Fang YH et al (2010) Elevated expression of TDP-43 in the forebrain of mice is sufficient to cause neurological and pathological phenotypes mimicking FTLD-U. J Exp Med 207:1661–1673PubMedGoogle Scholar
  25. 25.
    Shan X, Chiang PM, Price DL et al (2010) Altered distributions of Gemini of coiled bodies and mitochondria in motor neurons of TDP-43 transgenic mice. Proc Natl Acad Sci USA 107:16325–16330PubMedGoogle Scholar
  26. 26.
    Swarup V, Phaneuf D, Bareil C et al (2011) Pathological hallmarks of amyotrophic lateral sclerosis/frontotemporal lobar degeneration in transgenic mice produced with TDP-43 genomic fragments. Brain 134:2610–2626PubMedGoogle Scholar
  27. 27.
    Arnold ES, Ling SC, Huelga SC et al (2013) 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–E745PubMedGoogle Scholar
  28. 28.
    Uchida A, Sasaguri H, Kimura N et al (2012) Non-human primate model of amyotrophic lateral sclerosis with cytoplasmic mislocalization of TDP-43. Brain 135:833–846PubMedGoogle Scholar
  29. 29.
    Ling SC, Albuquerque CP, Han JS et al (2010) ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS. Proc Natl Acad Sci USA 107:13318–13323PubMedGoogle Scholar
  30. 30.
    Watanabe S, Kaneko K, Yamanaka K (2013) Accelerated disease onset with stabilized familial amyotrophic lateral sclerosis (ALS)-linked mutant TDP-43 proteins. J Biol Chem 288:3641–3654PubMedGoogle Scholar
  31. 31.
    Wu LS, Cheng WC, Hou SC et al (2010) TDP-43, a neuro-pathosignature factor, is essential for early mouse embryogenesis. Genesis 48:56–62PubMedGoogle Scholar
  32. 32.
    Sephton CF, Good SK, Atkin S et al (2010) TDP-43 is a developmentally regulated protein essential for early embryonic development. J Biol Chem 285:6826–6834PubMedGoogle Scholar
  33. 33.
    Kraemer BC, Schuck T, Wheeler JM et al (2010) Loss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis. Acta Neuropathol 119:409–419PubMedGoogle Scholar
  34. 34.
    Chiang PM, Ling J, Jeong YH et al (2010) Deletion of TDP-43 down-regulates Tbc1d1, a gene linked to obesity, and alters body fat metabolism. Proc Natl Acad Sci USA 107:16320–16324PubMedGoogle Scholar
  35. 35.
    Wu LS, Cheng WC, Shen CK (2012) 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 287:27335–27344PubMedGoogle Scholar
  36. 36.
    Iguchi Y, Katsuno M, Niwa J et al (2013) Loss of TDP-43 causes age-dependent progressive motor neuron degeneration. Brain 136:1371–1382PubMedGoogle Scholar
  37. 37.
    Kwiatkowski TJ Jr, Bosco DA, Leclerc AL et al (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323:1205–1208PubMedGoogle Scholar
  38. 38.
    Vance C, Rogelj B, Hortobagyi T et al (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323:1208–1211PubMedGoogle Scholar
  39. 39.
    Van Langenhove T, van der Zee J, Sleegers K et al (2010) Genetic contribution of FUS to frontotemporal lobar degeneration. Neurology 74:366–371PubMedGoogle Scholar
  40. 40.
    Yan J, Deng HX, Siddique N et al (2010) Frameshift and novel mutations in FUS in familial amyotrophic lateral sclerosis and ALS/dementia. Neurology 75:807–814PubMedGoogle Scholar
  41. 41.
    Mackenzie IR, Ansorge O, Strong M et al (2011) Pathological heterogeneity in amyotrophic lateral sclerosis with FUS mutations: two distinct patterns correlating with disease severity and mutation. Acta Neuropathol 122:87–98PubMedGoogle Scholar
  42. 42.
    Groen EJ, van Es MA, van Vught PW et al (2010) FUS mutations in familial amyotrophic lateral sclerosis in the Netherlands. Arch Neurol 67:224–230PubMedGoogle Scholar
  43. 43.
    Hara M, Minami M, Kamei S et al (2012) Lower motor neuron disease caused by a novel FUS/TLS gene frameshift mutation. J Neurol 259:2237–2239PubMedGoogle Scholar
  44. 44.
    Yamashita S, Mori A, Sakaguchi H et al (2012) Sporadic juvenile amyotrophic lateral sclerosis caused by mutant FUS/TLS: possible association of mental retardation with this mutation. J Neurol 259:1039–1044PubMedGoogle Scholar
  45. 45.
    Munoz DG, Neumann M, Kusaka H et al (2009) FUS pathology in basophilic inclusion body disease. Acta Neuropathol 118:617–627PubMedGoogle Scholar
  46. 46.
    Neumann M, Rademakers R, Roeber S et al (2009) A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 132:2922–2931PubMedGoogle Scholar
  47. 47.
    Neumann M, Roeber S, Kretzschmar HA et al (2009) Abundant FUS-immunoreactive pathology in neuronal intermediate filament inclusion disease. Acta Neuropathol 118:605–616PubMedGoogle Scholar
  48. 48.
    Seelaar H, Klijnsma KY, de Koning I et al (2010) Frequency of ubiquitin and FUS-positive, TDP-43-negative frontotemporal lobar degeneration. J Neurol 257:747–753PubMedGoogle Scholar
  49. 49.
    Tateishi T, Hokonohara T, Yamasaki R et al (2010) Multiple system degeneration with basophilic inclusions in Japanese ALS patients with FUS mutation. Acta Neuropathol 119:355–364PubMedGoogle Scholar
  50. 50.
    Suzuki N, Aoki M, Warita H et al (2010) FALS with FUS mutation in Japan, with early onset, rapid progress and basophilic inclusion. J Hum Genet 55:252–254PubMedGoogle Scholar
  51. 51.
    Deng HX, Zhai H, Bigio EH et al (2010) FUS-immunoreactive inclusions are a common feature in sporadic and non-SOD1 familial amyotrophic lateral sclerosis. Ann Neurol 67:739–748PubMedGoogle Scholar
  52. 52.
    Keller BA, Volkening K, Droppelmann CA et al (2012) Co-aggregation of RNA binding proteins in ALS spinal motor neurons: evidence of a common pathogenic mechanism. Acta Neuropathol 124:733–747PubMedGoogle Scholar
  53. 53.
    Huang EJ, Zhang J, Geser F et al (2010) Extensive FUS-immunoreactive pathology in juvenile amyotrophic lateral sclerosis with basophilic inclusions. Brain Pathol 20:1069–1076PubMedGoogle Scholar
  54. 54.
    Huang C, Zhou H, Tong J et al (2011) FUS transgenic rats develop the phenotypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. PLoS Genet 7:e1002011PubMedGoogle Scholar
  55. 55.
    Mitchell JC, McGoldrick P, Vance C et al (2013) Overexpression of human wild-type FUS causes progressive motor neuron degeneration in an age- and dose-dependent fashion. Acta Neuropathol 125:273–288PubMedGoogle Scholar
  56. 56.
    Hicks GG, Singh N, Nashabi A et al (2000) FUS deficiency in mice results in defective B-lymphocyte development and activation, high levels of chromosomal instability, and perinatal death. Nat Genet 24:175–179PubMedGoogle Scholar
  57. 57.
    Kuroda M, Sok J, Webb L et al (2000) Male sterility and enhanced radiation sensitivity in TLS (−/−) mice. EMBO J 19:453–462PubMedGoogle Scholar
  58. 58.
    Lagier–Tourenne C, Cleveland DW (2009) Rethinking ALS: the FUS about TDP-43. Cell 136:1001–1004PubMedGoogle Scholar
  59. 59.
    Ishigaki S, Masuda A, Fujioka Y et al (2012) Position-dependent FUS-RNA interactions regulate alternative splicing events and transcriptions. Sci Rep 2:529PubMedGoogle Scholar
  60. 60.
    Lagier–Tourenne C, Polymenidou M, Hutt KR et al (2012) Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs. Nat Neurosci 15:1488–1497PubMedGoogle Scholar
  61. 61.
    Rogelj B, Easton LE, Bogu GK et al (2012) Widespread binding of FUS along nascent RNA regulates alternative splicing in the brain. Sci Rep 2:603PubMedGoogle Scholar
  62. 62.
    Nakaya T, Alexiou P, Maragkakis M et al (2013) FUS regulates genes coding for RNA-binding proteins in neurons by binding to their highly conserved introns. RNA 19:498–509PubMedGoogle Scholar
  63. 63.
    Tsuiji H, Iguchi Y, Furuya A et al (2013) Spliceosome integrity is defective in the motor neuron diseases ALS and SMA. EMBO Mol Med 5:221–234PubMedGoogle Scholar
  64. 64.
    Yamazaki T, Chen S, Yu Y et al (2012) FUS-SMN protein interactions link the motor neuron diseases ALS and SMA. Cell Rep 2:799–806PubMedGoogle Scholar
  65. 65.
    Chow CY, Zhang Y, Dowling JJ et al (2007) Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4 J. Nature 448:68–72PubMedGoogle Scholar
  66. 66.
    Chow CY, Landers JE, Bergren SK et al (2009) Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS. Am J Hum Genet 84:85–88PubMedGoogle Scholar
  67. 67.
    Volpicelli–Daley L, De Camilli P (2007) Phosphoinositides’ link to neurodegeneration. Nat Med 13:784–786PubMedGoogle Scholar
  68. 68.
    Rutherford AC, Traer C, Wassmer T et al (2006) The mammalian phosphatidylinositol 3-phosphate 5-kinase (PIKfyve) regulates endosome-to-TGN retrograde transport. J Cell Sci 119:3944–3957PubMedGoogle Scholar
  69. 69.
    Zhang Y, Zolov SN, Chow CY et al (2007) Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice. Proc Natl Acad Sci USA 104:17518–17523PubMedGoogle Scholar
  70. 70.
    Ferguson CJ, Lenk GM, Meisler MH (2010) PtdIns(3,5)P2 and autophagy in mouse models of neurodegeneration. Autophagy 6:170–171PubMedGoogle Scholar
  71. 71.
    Ferguson CJ, Lenk GM, Meisler MH (2009) Defective autophagy in neurons and astrocytes from mice deficient in PI(3,5)P2. Hum Mol Genet 18:4868–4878PubMedGoogle Scholar
  72. 72.
    Maruyama H, Morino H, Ito H et al (2010) Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465:223–226PubMedGoogle Scholar
  73. 73.
    Del Bo R, Tiloca C, Pensato V et al (2011) Novel optineurin mutations in patients with familial and sporadic amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 82:1239–1243PubMedGoogle Scholar
  74. 74.
    Millecamps S, Boillee S, Chabrol E et al (2011) Screening of OPTN in French familial amyotrophic lateral sclerosis. Neurobiol Aging 32(557):e511–e553Google Scholar
  75. 75.
    Iida A, Hosono N, Sano M et al (2012) Optineurin mutations in Japanese amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 83:233–235PubMedGoogle Scholar
  76. 76.
    Zhu G, Wu CJ, Zhao Y et al (2007) Optineurin negatively regulates TNFα-induced NF-κB activation by competing with NEMO for ubiquitinated RIP. Curr Biol 17:1438–1443PubMedGoogle Scholar
  77. 77.
    Wild P, Farhan H, McEwan DG et al (2011) Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 333:228–233PubMedGoogle Scholar
  78. 78.
    Sahlender DA, Roberts RC, Arden SD et al (2005) Optineurin links myosin VI to the Golgi complex and is involved in Golgi organization and exocytosis. J Cell Biol 169:285–295PubMedGoogle Scholar
  79. 79.
    Deng HX, Bigio EH, Zhai H et al (2011) Differential involvement of optineurin in amyotrophic lateral sclerosis with or without SOD1 mutations. Arch Neurol 68:1057–1061PubMedGoogle Scholar
  80. 80.
    Hortobagyi T, Troakes C, Nishimura AL et al (2011) Optineurin inclusions occur in a minority of TDP-43 positive ALS and FTLD-TDP cases and are rarely observed in other neurodegenerative disorders. Acta Neuropathol 121:519–527PubMedGoogle Scholar
  81. 81.
    Osawa T, Mizuno Y, Fujita Y et al (2011) Optineurin in neurodegenerative diseases. Neuropathology 31:569–574PubMedGoogle Scholar
  82. 82.
    Elden AC, Kim HJ, Hart MP et al (2010) Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466:1069–1075PubMedGoogle Scholar
  83. 83.
    Lee T, Li YR, Ingre C et al (2011) Ataxin-2 intermediate-length polyglutamine expansions in European ALS patients. Hum Mol Genet 20:1697–1700PubMedGoogle Scholar
  84. 84.
    Daoud H, Belzil V, Martins S et al (2011) Association of long ATXN2 CAG repeat sizes with increased risk of amyotrophic lateral sclerosis. Arch Neurol 68:739–742PubMedGoogle Scholar
  85. 85.
    Gispert S, Kurz A, Waibel S et al (2012) The modulation of Amyotrophic Lateral Sclerosis risk by ataxin-2 intermediate polyglutamine expansions is a specific effect. Neurobiol Dis 45:356–361PubMedGoogle Scholar
  86. 86.
    Van Damme P, Veldink JH, van Blitterswijk M et al (2011) Expanded ATXN2 CAG repeat size in ALS identifies genetic overlap between ALS and SCA2. Neurology 76:2066–2072PubMedGoogle Scholar
  87. 87.
    Ross OA, Rutherford NJ, Baker M et al (2011) Ataxin-2 repeat-length variation and neurodegeneration. Hum Mol Genet 20:3207–3212PubMedGoogle Scholar
  88. 88.
    Farg MA, Soo KY, Warraich ST et al (2013) Ataxin-2 interacts with FUS and intermediate-length polyglutamine expansions enhance FUS-related pathology in amyotrophic lateral sclerosis. Hum Mol Genet 22:717–728PubMedGoogle Scholar
  89. 89.
    Henneberger C, Papouin T, Oliet SH et al (2010) Long-term potentiation depends on release of d-serine from astrocytes. Nature 463:232–236PubMedGoogle Scholar
  90. 90.
    Sasabe J, Chiba T, Yamada M et al (2007) d-serine is a key determinant of glutamate toxicity in amyotrophic lateral sclerosis. EMBO J 26:4149–4159PubMedGoogle Scholar
  91. 91.
    Sasabe J, Miyoshi Y, Suzuki M et al (2012) d-amino acid oxidase controls motoneuron degeneration through d-serine. Proc Natl Acad Sci USA 109:627–632PubMedGoogle Scholar
  92. 92.
    Mitchell J, Paul P, Chen HJ et al (2010) Familial amyotrophic lateral sclerosis is associated with a mutation in d-amino acid oxidase. Proc Natl Acad Sci USA 107:7556–7561PubMedGoogle Scholar
  93. 93.
    Stevanin G, Santorelli FM, Azzedine H et al (2007) Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum. Nat Genet 39:366–372PubMedGoogle Scholar
  94. 94.
    Orlacchio A, Babalini C, Borreca A et al (2010) SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis. Brain 133:591–598PubMedGoogle Scholar
  95. 95.
    Watts GD, Wymer J, Kovach MJ et al (2004) Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet 36:377–381PubMedGoogle Scholar
  96. 96.
    Johnson JO, Mandrioli J, Benatar M et al (2010) Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68:857–864PubMedGoogle Scholar
  97. 97.
    Rohrer JD, Warren JD, Reiman D et al (2011) A novel exon 2 I27V VCP variant is associated with dissimilar clinical syndromes. J Neurol 258:1494–1496PubMedGoogle Scholar
  98. 98.
    Neumann M, Mackenzie IR, Cairns NJ et al (2007) TDP-43 in the ubiquitin pathology of frontotemporal dementia with VCP gene mutations. J Neuropathol Exp Neurol 66:152–157PubMedGoogle Scholar
  99. 99.
    Meyer H, Bug M, Bremer S (2012) Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system. Nat Cell Biol 14:117–123PubMedGoogle Scholar
  100. 100.
    Ju JS, Fuentealba RA, Miller SE et al (2009) Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease. J Cell Biol 187:875–888PubMedGoogle Scholar
  101. 101.
    Badadani M, Nalbandian A, Watts GD et al (2010) VCP associated inclusion body myopathy and paget disease of bone knock-in mouse model exhibits tissue pathology typical of human disease. PLoS One 5. doi:  10.1371/journal.pone.0013183
  102. 102.
    Custer SK, Neumann M, Lu H et al (2010) Transgenic mice expressing mutant forms VCP/p97 recapitulate the full spectrum of IBMPFD including degeneration in muscle, brain, and bone. Hum Mol Genet 19:1741–1755PubMedGoogle Scholar
  103. 103.
    Yin HZ, Nalbandian A, Hsu CI et al (2012) Slow development of ALS-like spinal cord pathology in mutant valosin-containing protein gene knock-in mice. Cell Death Dis 3:e374PubMedGoogle Scholar
  104. 104.
    Deng HX, Chen W, Hong ST et al (2011) Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 477:211–215PubMedGoogle Scholar
  105. 105.
    Williams KL, Warraich ST, Yang S et al (2012) UBQLN2/ubiquilin 2 mutation and pathology in familial amyotrophic lateral sclerosis. Neurobiol Aging 33:2527 e2523–2510Google Scholar
  106. 106.
    Rothenberg C, Srinivasan D, Mah L et al (2010) Ubiquilin functions in autophagy and is degraded by chaperone-mediated autophagy. Hum Mol Genet 19:3219–3232PubMedGoogle Scholar
  107. 107.
    Lee DY, Brown EJ (2012) Ubiquilins in the crosstalk among proteolytic pathways. Biol Chem 393:441–447PubMedGoogle Scholar
  108. 108.
    DeJesus-Hernandez M, Mackenzie IR, Boeve BF et al (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72:245–256PubMedGoogle Scholar
  109. 109.
    Renton AE, Majounie E, Waite A et al (2011) A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72:257–268PubMedGoogle Scholar
  110. 110.
    Beck J, Poulter M, Hensman D et al (2013) Large C9orf72 hexanucleotide repeat expansions are seen in multiple neurodegenerative syndromes and are more frequent than expected in the UK population. Am J Hum Genet 92:345–353PubMedGoogle Scholar
  111. 111.
    Cruts M, Gijselinck I, Van Langenhove T et al (2013) Current insights into the C9orf72 repeat expansion diseases of the FTLD/ALS spectrum. Trends NeurosciGoogle Scholar
  112. 112.
    Smith BN, Newhouse S, Shatunov A et al (2013) The C9ORF72 expansion mutation is a common cause of ALS ± FTD in Europe and has a single founder. Eur J Hum Genet 21:102–108PubMedGoogle Scholar
  113. 113.
    Majounie E, Renton AE, Mok K et al (2012) Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol 11:323–330PubMedGoogle Scholar
  114. 114.
    Tsai CP, Soong BW, Tu PH et al (2012) A hexanucleotide repeat expansion in C9ORF72 causes familial and sporadic ALS in Taiwan. Neurobiol Aging 33:2232.e2211–2232.e2218Google Scholar
  115. 115.
    Ishiura H, Takahashi Y, Mitsui J et al (2012) C9ORF72 repeat expansion in amyotrophic lateral sclerosis in the Kii peninsula of Japan. Arch Neurol 69:1154–1158PubMedGoogle Scholar
  116. 116.
    Ogaki K, Li Y, Atsuta N et al (2012) Analysis of C9orf72 repeat expansion in 563 Japanese patients with amyotrophic lateral sclerosis. Neurobiol Aging 33(2527):e2511–e2526Google Scholar
  117. 117.
    Konno T, Shiga A, Tsujino A et al (2013) Japanese amyotrophic lateral sclerosis patients with GGGGCC hexanucleotide repeat expansion in C9ORF72. J Neurol Neurosurg Psychiatry 84:398–401PubMedGoogle Scholar
  118. 118.
    Jang JH, Kwon MJ, Choi WJ et al (2013) Analysis of the C9orf72 hexanucleotide repeat expansion in Korean patients with familial and sporadic amyotrophic lateral sclerosis. Neurobiol Aging 34(1311):e1317–e1319Google Scholar
  119. 119.
    Zou ZY, Li XG, Liu MS et al (2013) Screening for C9orf72 repeat expansions in Chinese amyotrophic lateral sclerosis patients. Neurobiol Aging 34(1710):e1715–e1716Google Scholar
  120. 120.
    Byrne S, Elamin M, Bede P et al (2012) Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study. Lancet Neurol 11:232–240PubMedGoogle Scholar
  121. 121.
    Floris G, Borghero G, Cannas A et al (2012) Frontotemporal dementia with psychosis, parkinsonism, visuo-spatial dysfunction, upper motor neuron involvement associated to expansion of C9ORF72: a peculiar phenotype? J Neurol 259:1749–1751PubMedGoogle Scholar
  122. 122.
    Calvo A, Moglia C, Canosa A et al (2012) Amyotrophic lateral sclerosis/frontotemporal dementia with predominant manifestations of obsessive-compulsive disorder associated to GGGGCC expansion of the c9orf72 gene. J Neurol 259:2723–2725PubMedGoogle Scholar
  123. 123.
    Al-Sarraj S, King A, Troakes C et al (2011) 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 122:691–702PubMedGoogle Scholar
  124. 124.
    Brettschneider J, Van Deerlin VM, Robinson JL et al (2012) Pattern of ubiquilin pathology in ALS and FTLD indicates presence of C9ORF72 hexanucleotide expansion. Acta Neuropathol 123:825–839PubMedGoogle Scholar
  125. 125.
    Mori K, Weng SM, Arzberger T et al (2013) The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339:1335–1338PubMedGoogle Scholar
  126. 126.
    Ash PE, Bieniek KF, Gendron TF et al (2013) Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 77:639–646PubMedGoogle Scholar
  127. 127.
    Levine TP, Daniels RD, Gatta AT et al (2013) The product of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFs. Bioinformatics 29:499–503PubMedGoogle Scholar
  128. 128.
    Gijselinck I, Van Langenhove T, van der Zee J et al (2012) 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 11:54–65PubMedGoogle Scholar
  129. 129.
    Wu CH, Fallini C, Ticozzi N et al (2012) Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 488:499–503PubMedGoogle Scholar
  130. 130.
    Zou ZY, Sun Q, Liu MS et al (2013) Mutations in the profilin 1 gene are not common in amyotrophic lateral sclerosis of Chinese origin. Neurobiol Aging 34(1713):e1715–e1716Google Scholar
  131. 131.
    van Blitterswijk M, Baker MC, Bieniek KF et al (2013) Profilin-1 mutations are rare in patients with amyotrophic lateral sclerosis and frontotemporal dementia. Amyotroph Lateral Scler Frontotemporal DegenerGoogle Scholar
  132. 132.
    Tiloca C, Ticozzi N, Pensato V et al (2013) Screening of the PFN1 gene in sporadic amyotrophic lateral sclerosis and in frontotemporal dementia. Neurobiol Aging 34:1517 e1519–1510Google Scholar
  133. 133.
    Lattante S, Le Ber I, Camuzat A et al (2013) Mutations in the PFN1 gene are not a common cause in patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration in France. Neurobiol Aging 34(1709):e1701–e1702Google Scholar
  134. 134.
    Ingre C, Landers JE, Rizik N et al (2013) A novel phosphorylation site mutation in profilin 1 revealed in a large screen of US, Nordic, and German amyotrophic lateral sclerosis/frontotemporal dementia cohorts. Neurobiol Aging 34(1708):e1701–e1706Google Scholar
  135. 135.
    Dillen L, Van Langenhove T, Engelborghs S et al (2013) Explorative genetic study of UBQLN2 and PFN1 in an extended Flanders-Belgian cohort of frontotemporal lobar degeneration patients. Neurobiol Aging 34(1711):e1711–e1715Google Scholar
  136. 136.
    Daoud H, Dobrzeniecka S, Camu W et al (2013) Mutation analysis of PFN1 in familial amyotrophic lateral sclerosis patients. Neurobiol Aging 34(1311):e1311–e1312Google Scholar
  137. 137.
    Chen Y, Zheng ZZ, Huang R et al (2013) PFN1 mutations are rare in Han Chinese populations with amyotrophic lateral sclerosis. Neurobiol Aging 34(1922):e1921–e1925Google Scholar
  138. 138.
    Yang S, Fifita JA, Williams KL et al (2013) Mutation analysis and immunopathological studies of PFN1 in familial and sporadic amyotrophic lateral sclerosis. Neurobiol Aging 34:2235.e2237–2235.e2210Google Scholar
  139. 139.
    Mockrin SC, Korn ED (1980) Acanthamoeba profilin interacts with G-actin to increase the rate of exchange of actin-bound adenosine 5′-triphosphate. Biochemistry 19:5359–5362PubMedGoogle Scholar
  140. 140.
    Wills Z, Marr L, Zinn K et al (1999) Profilin and the Abl tyrosine kinase are required for motor axon outgrowth in the Drosophila embryo. Neuron 22:291–299PubMedGoogle Scholar
  141. 141.
    Al-Saif A, Al-Mohanna F, Bohlega S (2011) A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis. Ann Neurol 70:913–919PubMedGoogle Scholar
  142. 142.
    Hayashi T, Su TP (2007) Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell 131:596–610PubMedGoogle Scholar
  143. 143.
    Mavlyutov TA, Epstein ML, Andersen KA et al (2010) The sigma-1 receptor is enriched in postsynaptic sites of C-terminals in mouse motoneurons. An anatomical and behavioral study. Neuroscience 167:247–255PubMedGoogle Scholar
  144. 144.
    Katsuno M, Tanaka F, Sobue G (2012) Perspectives on molecular targeted therapies and clinical trials for neurodegenerative diseases. J Neurol Neurosurg Psychiatry 83:329–335PubMedGoogle Scholar
  145. 145.
    Miller RG, Mitchell JD, Moore DH (2012) Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev 3:CD001447Google Scholar
  146. 146.
    Mackenzie IR, Bigio EH, Ince PG et al (2007) Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol 61:427–434PubMedGoogle Scholar
  147. 147.
    Tan CF, Eguchi H, Tagawa A et al (2007) TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation. Acta Neuropathol 113:535–542PubMedGoogle Scholar
  148. 148.
    Egawa N, Kitaoka S, Tsukita K et al (2012) Drug screening for ALS using patient-specific induced pluripotent stem cells. Sci Transl Med 4:145ra104Google Scholar
  149. 149.
    Fecto F, Yan J, Vemula SP et al (2011) SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch Neurol 68:1440–1446PubMedGoogle Scholar
  150. 150.
    Sasaki S (2011) Autophagy in spinal cord motor neurons in sporadic amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 70:349–359PubMedGoogle Scholar
  151. 151.
    Wang IF, Guo BS, Liu YC et al (2012) Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43. Proc Natl Acad Sci USA 109:15024–15029PubMedGoogle Scholar
  152. 152.
    Anderson P, Kedersha N (2008) Stress granules: the Tao of RNA triage. Trends Biochem Sci 33:141–150PubMedGoogle Scholar
  153. 153.
    Colombrita C, Zennaro E, Fallini C et al (2009) TDP-43 is recruited to stress granules in conditions of oxidative insult. J Neurochem 111:1051–1061PubMedGoogle Scholar
  154. 154.
    Andersson MK, Stahlberg A, Arvidsson Y et al (2008) The multifunctional FUS, EWS and TAF15 proto-oncoproteins show cell type-specific expression patterns and involvement in cell spreading and stress response. BMC Cell Biol 9:37PubMedGoogle Scholar
  155. 155.
    Nonhoff U, Ralser M, Welzel F et al (2007) Ataxin-2 interacts with the DEAD/H-box RNA helicase DDX6 and interferes with P-bodies and stress granules. Mol Biol Cell 18:1385–1396PubMedGoogle Scholar
  156. 156.
    Nishimoto Y, Ito D, Yagi T et al (2010) Characterization of alternative isoforms and inclusion body of the TAR DNA-binding protein-43. J Biol Chem 285:608–619PubMedGoogle Scholar
  157. 157.
    Bosco DA, Lemay N, Ko HK et al (2010) Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules. Hum Mol Genet 19:4160–4175PubMedGoogle Scholar
  158. 158.
    Dormann D, Rodde R, Edbauer D et al (2010) ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import. EMBO J 29:2841–2857PubMedGoogle Scholar
  159. 159.
    Liu-Yesucevitz L, Bilgutay A, Zhang YJ et al (2010) Tar DNA binding protein-43 (TDP-43) associates with stress granules: analysis of cultured cells and pathological brain tissue. PLoS One 5:e13250PubMedGoogle Scholar
  160. 160.
    Nonaka T, Masuda-Suzukake M, Arai T et al (2013) Prion-like properties of pathological TDP-43 aggregates from diseased brains. Cell Rep 4:124–134PubMedGoogle Scholar
  161. 161.
    Couthouis J, Hart MP, Shorter J et al (2011) A yeast functional screen predicts new candidate ALS disease genes. Proc Natl Acad Sci USA 108:20881–20890PubMedGoogle Scholar
  162. 162.
    Couthouis J, Hart MP, Erion R et al (2012) Evaluating the role of the FUS/TLS-related gene EWSR1 in amyotrophic lateral sclerosis. Hum Mol Genet 21:2899–2911PubMedGoogle Scholar
  163. 163.
    Kim HJ, Kim NC, Wang YD et al (2013) Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495:467–473PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Yohei Iguchi
    • 1
    • 2
  • Masahisa Katsuno
    • 1
  • Kensuke Ikenaka
    • 1
  • Shinsuke Ishigaki
    • 1
  • Gen Sobue
    • 1
    Email author
  1. 1.Department of NeurologyNagoya University Graduate School of MedicineNagoyaJapan
  2. 2.The Centre de Recherche de l’Institut Universitaire en Santé Mentale de Québec-CRIUSMQLaval UniversityQuebecCanada

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