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Published in: Journal of Neurology 11/2013

01-11-2013 | Medical Progress in the Journal of Neurology

Amyotrophic lateral sclerosis: an update on recent genetic insights

Authors: Yohei Iguchi, Masahisa Katsuno, Kensuke Ikenaka, Shinsuke Ishigaki, Gen Sobue

Published in: Journal of Neurology | Issue 11/2013

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Abstract

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.
Literature
1.
go back to reference 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 351:602–611PubMed 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 351:602–611PubMed
2.
go back to reference Neumann M, Sampathu DM, Kwong LK et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133PubMed Neumann M, Sampathu DM, Kwong LK et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133PubMed
3.
go back to reference Mackenzie IR, Neumann M, Cairns NJ et al (2011) Novel types of frontotemporal lobar degeneration: beyond tau and TDP-43. J Mol Neurosci 45:402–408PubMed Mackenzie IR, Neumann M, Cairns NJ et al (2011) Novel types of frontotemporal lobar degeneration: beyond tau and TDP-43. J Mol Neurosci 45:402–408PubMed
4.
go back to reference Gitcho MA, Baloh RH, Chakraverty S et al (2008) TDP-43 A315T mutation in familial motor neuron disease. Ann Neurol 63:535–538PubMed Gitcho MA, Baloh RH, Chakraverty S et al (2008) TDP-43 A315T mutation in familial motor neuron disease. Ann Neurol 63:535–538PubMed
5.
go back to reference Kabashi E, Valdmanis PN, Dion P et al (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 40:572–574PubMed Kabashi E, Valdmanis PN, Dion P et al (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 40:572–574PubMed
6.
go back to reference Sreedharan J, Blair IP, Tripathi VB et al (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319:1668–1672PubMed Sreedharan J, Blair IP, Tripathi VB et al (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319:1668–1672PubMed
7.
go back to reference Yokoseki A, Shiga A, Tan CF et al (2008) TDP-43 mutation in familial amyotrophic lateral sclerosis. Ann Neurol 63:538–542PubMed Yokoseki A, Shiga A, Tan CF et al (2008) TDP-43 mutation in familial amyotrophic lateral sclerosis. Ann Neurol 63:538–542PubMed
8.
go back to reference Corcia P, Valdmanis P, Millecamps S et al (2012) Phenotype and genotype analysis in amyotrophic lateral sclerosis with TARDBP gene mutations. Neurology 78:1519–1526PubMed Corcia P, Valdmanis P, Millecamps S et al (2012) Phenotype and genotype analysis in amyotrophic lateral sclerosis with TARDBP gene mutations. Neurology 78:1519–1526PubMed
9.
go back to reference Wang HY, Wang IF, Bose J et al (2004) Structural diversity and functional implications of the eukaryotic TDP gene family. Genomics 83:130–139PubMed Wang HY, Wang IF, Bose J et al (2004) Structural diversity and functional implications of the eukaryotic TDP gene family. Genomics 83:130–139PubMed
10.
go back to reference 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 348:575–588PubMed 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 348:575–588PubMed
11.
go back to reference 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 280:37572–37584PubMed 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 280:37572–37584PubMed
12.
go back to reference Strong MJ, Volkening K, Hammond R et al (2007) TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein. Mol Cell Neurosci 35:320–327PubMed Strong MJ, Volkening K, Hammond R et al (2007) TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein. Mol Cell Neurosci 35:320–327PubMed
13.
go back to reference Buratti E, De Conti L, Stuani C et al (2010) Nuclear factor TDP-43 can affect selected microRNA levels. FEBS J 277:2268–2281PubMed Buratti E, De Conti L, Stuani C et al (2010) Nuclear factor TDP-43 can affect selected microRNA levels. FEBS J 277:2268–2281PubMed
14.
go back to reference 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 14:459–468PubMed 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 14:459–468PubMed
15.
go back to reference Tollervey JR, Curk T, Rogelj B et al (2011) Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat Neurosci 14:452–458PubMed Tollervey JR, Curk T, Rogelj B et al (2011) Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat Neurosci 14:452–458PubMed
16.
go back to reference Sephton CF, Cenik C, Kucukural A et al (2011) Identification of neuronal RNA targets of TDP-43-containing ribonucleoprotein complexes. J Biol Chem 286:1204–1215PubMed Sephton CF, Cenik C, Kucukural A et al (2011) Identification of neuronal RNA targets of TDP-43-containing ribonucleoprotein complexes. J Biol Chem 286:1204–1215PubMed
17.
go back to reference 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 47:167–180PubMed 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 47:167–180PubMed
18.
go back to reference 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 109:3347–3352PubMed 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 109:3347–3352PubMed
19.
go back to reference 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 106:18809–18814PubMed 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 106:18809–18814PubMed
20.
go back to reference 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 107:3858–3863PubMed 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 107:3858–3863PubMed
21.
go back to reference 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 30:10851–10859PubMed 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 30:10851–10859PubMed
22.
go back to reference Stallings NR, Puttaparthi K, Luther CM et al (2010) Progressive motor weakness in transgenic mice expressing human TDP-43. Neurobiol Dis 40:404–414PubMed Stallings NR, Puttaparthi K, Luther CM et al (2010) Progressive motor weakness in transgenic mice expressing human TDP-43. Neurobiol Dis 40:404–414PubMed
23.
go back to reference Zhou H, Huang C, Chen H et al (2010) Transgenic rat model of neurodegeneration caused by mutation in the TDP gene. PLoS Genet 6:e1000887PubMed Zhou H, Huang C, Chen H et al (2010) Transgenic rat model of neurodegeneration caused by mutation in the TDP gene. PLoS Genet 6:e1000887PubMed
24.
go back to reference 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 207:1661–1673PubMed 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 207:1661–1673PubMed
25.
go back to reference 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 107:16325–16330PubMed 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 107:16325–16330PubMed
26.
go back to reference 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 134:2610–2626PubMed 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 134:2610–2626PubMed
27.
go back to reference 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–E745PubMed 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–E745PubMed
28.
go back to reference Uchida A, Sasaguri H, Kimura N et al (2012) Non-human primate model of amyotrophic lateral sclerosis with cytoplasmic mislocalization of TDP-43. Brain 135:833–846PubMed Uchida A, Sasaguri H, Kimura N et al (2012) Non-human primate model of amyotrophic lateral sclerosis with cytoplasmic mislocalization of TDP-43. Brain 135:833–846PubMed
29.
go back to reference 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 107:13318–13323PubMed 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 107:13318–13323PubMed
30.
go back to reference 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 288:3641–3654PubMed 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 288:3641–3654PubMed
31.
go back to reference Wu LS, Cheng WC, Hou SC et al (2010) TDP-43, a neuro-pathosignature factor, is essential for early mouse embryogenesis. Genesis 48:56–62PubMed Wu LS, Cheng WC, Hou SC et al (2010) TDP-43, a neuro-pathosignature factor, is essential for early mouse embryogenesis. Genesis 48:56–62PubMed
32.
go back to reference Sephton CF, Good SK, Atkin S et al (2010) TDP-43 is a developmentally regulated protein essential for early embryonic development. J Biol Chem 285:6826–6834PubMed Sephton CF, Good SK, Atkin S et al (2010) TDP-43 is a developmentally regulated protein essential for early embryonic development. J Biol Chem 285:6826–6834PubMed
33.
go back to reference 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 119:409–419PubMed 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 119:409–419PubMed
34.
go back to reference 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 107:16320–16324PubMed 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 107:16320–16324PubMed
35.
go back to reference 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 287:27335–27344PubMed 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 287:27335–27344PubMed
36.
go back to reference Iguchi Y, Katsuno M, Niwa J et al (2013) Loss of TDP-43 causes age-dependent progressive motor neuron degeneration. Brain 136:1371–1382PubMed Iguchi Y, Katsuno M, Niwa J et al (2013) Loss of TDP-43 causes age-dependent progressive motor neuron degeneration. Brain 136:1371–1382PubMed
37.
go back to reference 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 323:1205–1208PubMed 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 323:1205–1208PubMed
38.
go back to reference Vance C, Rogelj B, Hortobagyi T et al (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323:1208–1211PubMed Vance C, Rogelj B, Hortobagyi T et al (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323:1208–1211PubMed
39.
go back to reference Van Langenhove T, van der Zee J, Sleegers K et al (2010) Genetic contribution of FUS to frontotemporal lobar degeneration. Neurology 74:366–371PubMed Van Langenhove T, van der Zee J, Sleegers K et al (2010) Genetic contribution of FUS to frontotemporal lobar degeneration. Neurology 74:366–371PubMed
40.
go back to reference Yan J, Deng HX, Siddique N et al (2010) Frameshift and novel mutations in FUS in familial amyotrophic lateral sclerosis and ALS/dementia. Neurology 75:807–814PubMed Yan J, Deng HX, Siddique N et al (2010) Frameshift and novel mutations in FUS in familial amyotrophic lateral sclerosis and ALS/dementia. Neurology 75:807–814PubMed
41.
go back to reference 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 122:87–98PubMed 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 122:87–98PubMed
42.
go back to reference Groen EJ, van Es MA, van Vught PW et al (2010) FUS mutations in familial amyotrophic lateral sclerosis in the Netherlands. Arch Neurol 67:224–230PubMed Groen EJ, van Es MA, van Vught PW et al (2010) FUS mutations in familial amyotrophic lateral sclerosis in the Netherlands. Arch Neurol 67:224–230PubMed
43.
go back to reference Hara M, Minami M, Kamei S et al (2012) Lower motor neuron disease caused by a novel FUS/TLS gene frameshift mutation. J Neurol 259:2237–2239PubMed Hara M, Minami M, Kamei S et al (2012) Lower motor neuron disease caused by a novel FUS/TLS gene frameshift mutation. J Neurol 259:2237–2239PubMed
44.
go back to reference 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 259:1039–1044PubMed 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 259:1039–1044PubMed
45.
go back to reference Munoz DG, Neumann M, Kusaka H et al (2009) FUS pathology in basophilic inclusion body disease. Acta Neuropathol 118:617–627PubMed Munoz DG, Neumann M, Kusaka H et al (2009) FUS pathology in basophilic inclusion body disease. Acta Neuropathol 118:617–627PubMed
46.
go back to reference Neumann M, Rademakers R, Roeber S et al (2009) A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 132:2922–2931PubMed Neumann M, Rademakers R, Roeber S et al (2009) A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 132:2922–2931PubMed
47.
go back to reference Neumann M, Roeber S, Kretzschmar HA et al (2009) Abundant FUS-immunoreactive pathology in neuronal intermediate filament inclusion disease. Acta Neuropathol 118:605–616PubMed Neumann M, Roeber S, Kretzschmar HA et al (2009) Abundant FUS-immunoreactive pathology in neuronal intermediate filament inclusion disease. Acta Neuropathol 118:605–616PubMed
48.
go back to reference Seelaar H, Klijnsma KY, de Koning I et al (2010) Frequency of ubiquitin and FUS-positive, TDP-43-negative frontotemporal lobar degeneration. J Neurol 257:747–753PubMed Seelaar H, Klijnsma KY, de Koning I et al (2010) Frequency of ubiquitin and FUS-positive, TDP-43-negative frontotemporal lobar degeneration. J Neurol 257:747–753PubMed
49.
go back to reference Tateishi T, Hokonohara T, Yamasaki R et al (2010) Multiple system degeneration with basophilic inclusions in Japanese ALS patients with FUS mutation. Acta Neuropathol 119:355–364PubMed Tateishi T, Hokonohara T, Yamasaki R et al (2010) Multiple system degeneration with basophilic inclusions in Japanese ALS patients with FUS mutation. Acta Neuropathol 119:355–364PubMed
50.
go back to reference 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 55:252–254PubMed 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 55:252–254PubMed
51.
go back to reference 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 67:739–748PubMed 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 67:739–748PubMed
52.
go back to reference 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 124:733–747PubMed 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 124:733–747PubMed
53.
go back to reference Huang EJ, Zhang J, Geser F et al (2010) Extensive FUS-immunoreactive pathology in juvenile amyotrophic lateral sclerosis with basophilic inclusions. Brain Pathol 20:1069–1076PubMed Huang EJ, Zhang J, Geser F et al (2010) Extensive FUS-immunoreactive pathology in juvenile amyotrophic lateral sclerosis with basophilic inclusions. Brain Pathol 20:1069–1076PubMed
54.
go back to reference 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:e1002011PubMed 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:e1002011PubMed
55.
go back to reference 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 125:273–288PubMed 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 125:273–288PubMed
56.
go back to reference 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 24:175–179PubMed 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 24:175–179PubMed
57.
go back to reference Kuroda M, Sok J, Webb L et al (2000) Male sterility and enhanced radiation sensitivity in TLS (−/−) mice. EMBO J 19:453–462PubMed Kuroda M, Sok J, Webb L et al (2000) Male sterility and enhanced radiation sensitivity in TLS (−/−) mice. EMBO J 19:453–462PubMed
58.
go back to reference Lagier–Tourenne C, Cleveland DW (2009) Rethinking ALS: the FUS about TDP-43. Cell 136:1001–1004PubMed Lagier–Tourenne C, Cleveland DW (2009) Rethinking ALS: the FUS about TDP-43. Cell 136:1001–1004PubMed
59.
go back to reference Ishigaki S, Masuda A, Fujioka Y et al (2012) Position-dependent FUS-RNA interactions regulate alternative splicing events and transcriptions. Sci Rep 2:529PubMed Ishigaki S, Masuda A, Fujioka Y et al (2012) Position-dependent FUS-RNA interactions regulate alternative splicing events and transcriptions. Sci Rep 2:529PubMed
60.
go back to reference 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 15:1488–1497PubMed 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 15:1488–1497PubMed
61.
go back to reference Rogelj B, Easton LE, Bogu GK et al (2012) Widespread binding of FUS along nascent RNA regulates alternative splicing in the brain. Sci Rep 2:603PubMed Rogelj B, Easton LE, Bogu GK et al (2012) Widespread binding of FUS along nascent RNA regulates alternative splicing in the brain. Sci Rep 2:603PubMed
62.
go back to reference 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 19:498–509PubMed 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 19:498–509PubMed
63.
go back to reference Tsuiji H, Iguchi Y, Furuya A et al (2013) Spliceosome integrity is defective in the motor neuron diseases ALS and SMA. EMBO Mol Med 5:221–234PubMed Tsuiji H, Iguchi Y, Furuya A et al (2013) Spliceosome integrity is defective in the motor neuron diseases ALS and SMA. EMBO Mol Med 5:221–234PubMed
64.
go back to reference Yamazaki T, Chen S, Yu Y et al (2012) FUS-SMN protein interactions link the motor neuron diseases ALS and SMA. Cell Rep 2:799–806PubMed Yamazaki T, Chen S, Yu Y et al (2012) FUS-SMN protein interactions link the motor neuron diseases ALS and SMA. Cell Rep 2:799–806PubMed
65.
go back to reference 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 448:68–72PubMed 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 448:68–72PubMed
66.
go back to reference Chow CY, Landers JE, Bergren SK et al (2009) Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS. Am J Hum Genet 84:85–88PubMed Chow CY, Landers JE, Bergren SK et al (2009) Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS. Am J Hum Genet 84:85–88PubMed
67.
go back to reference Volpicelli–Daley L, De Camilli P (2007) Phosphoinositides’ link to neurodegeneration. Nat Med 13:784–786PubMed Volpicelli–Daley L, De Camilli P (2007) Phosphoinositides’ link to neurodegeneration. Nat Med 13:784–786PubMed
68.
go back to reference 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 119:3944–3957PubMed 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 119:3944–3957PubMed
69.
go back to reference 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 104:17518–17523PubMed 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 104:17518–17523PubMed
70.
go back to reference Ferguson CJ, Lenk GM, Meisler MH (2010) PtdIns(3,5)P2 and autophagy in mouse models of neurodegeneration. Autophagy 6:170–171PubMed Ferguson CJ, Lenk GM, Meisler MH (2010) PtdIns(3,5)P2 and autophagy in mouse models of neurodegeneration. Autophagy 6:170–171PubMed
71.
go back to reference Ferguson CJ, Lenk GM, Meisler MH (2009) Defective autophagy in neurons and astrocytes from mice deficient in PI(3,5)P2. Hum Mol Genet 18:4868–4878PubMed Ferguson CJ, Lenk GM, Meisler MH (2009) Defective autophagy in neurons and astrocytes from mice deficient in PI(3,5)P2. Hum Mol Genet 18:4868–4878PubMed
72.
go back to reference Maruyama H, Morino H, Ito H et al (2010) Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465:223–226PubMed Maruyama H, Morino H, Ito H et al (2010) Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465:223–226PubMed
73.
go back to reference 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 82:1239–1243PubMed 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 82:1239–1243PubMed
74.
go back to reference Millecamps S, Boillee S, Chabrol E et al (2011) Screening of OPTN in French familial amyotrophic lateral sclerosis. Neurobiol Aging 32(557):e511–e553 Millecamps S, Boillee S, Chabrol E et al (2011) Screening of OPTN in French familial amyotrophic lateral sclerosis. Neurobiol Aging 32(557):e511–e553
75.
go back to reference Iida A, Hosono N, Sano M et al (2012) Optineurin mutations in Japanese amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 83:233–235PubMed Iida A, Hosono N, Sano M et al (2012) Optineurin mutations in Japanese amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 83:233–235PubMed
76.
go back to reference 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 17:1438–1443PubMed 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 17:1438–1443PubMed
77.
go back to reference Wild P, Farhan H, McEwan DG et al (2011) Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 333:228–233PubMed Wild P, Farhan H, McEwan DG et al (2011) Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 333:228–233PubMed
78.
go back to reference 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 169:285–295PubMed 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 169:285–295PubMed
79.
go back to reference Deng HX, Bigio EH, Zhai H et al (2011) Differential involvement of optineurin in amyotrophic lateral sclerosis with or without SOD1 mutations. Arch Neurol 68:1057–1061PubMed Deng HX, Bigio EH, Zhai H et al (2011) Differential involvement of optineurin in amyotrophic lateral sclerosis with or without SOD1 mutations. Arch Neurol 68:1057–1061PubMed
80.
go back to reference 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 121:519–527PubMed 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 121:519–527PubMed
81.
go back to reference Osawa T, Mizuno Y, Fujita Y et al (2011) Optineurin in neurodegenerative diseases. Neuropathology 31:569–574PubMed Osawa T, Mizuno Y, Fujita Y et al (2011) Optineurin in neurodegenerative diseases. Neuropathology 31:569–574PubMed
82.
go back to reference Elden AC, Kim HJ, Hart MP et al (2010) Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466:1069–1075PubMed Elden AC, Kim HJ, Hart MP et al (2010) Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466:1069–1075PubMed
83.
go back to reference Lee T, Li YR, Ingre C et al (2011) Ataxin-2 intermediate-length polyglutamine expansions in European ALS patients. Hum Mol Genet 20:1697–1700PubMed Lee T, Li YR, Ingre C et al (2011) Ataxin-2 intermediate-length polyglutamine expansions in European ALS patients. Hum Mol Genet 20:1697–1700PubMed
84.
go back to reference 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 68:739–742PubMed 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 68:739–742PubMed
85.
go back to reference 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 45:356–361PubMed 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 45:356–361PubMed
86.
go back to reference 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 76:2066–2072PubMed 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 76:2066–2072PubMed
87.
go back to reference Ross OA, Rutherford NJ, Baker M et al (2011) Ataxin-2 repeat-length variation and neurodegeneration. Hum Mol Genet 20:3207–3212PubMed Ross OA, Rutherford NJ, Baker M et al (2011) Ataxin-2 repeat-length variation and neurodegeneration. Hum Mol Genet 20:3207–3212PubMed
88.
go back to reference 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 22:717–728PubMed 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 22:717–728PubMed
89.
go back to reference Henneberger C, Papouin T, Oliet SH et al (2010) Long-term potentiation depends on release of d-serine from astrocytes. Nature 463:232–236PubMed Henneberger C, Papouin T, Oliet SH et al (2010) Long-term potentiation depends on release of d-serine from astrocytes. Nature 463:232–236PubMed
90.
go back to reference Sasabe J, Chiba T, Yamada M et al (2007) d-serine is a key determinant of glutamate toxicity in amyotrophic lateral sclerosis. EMBO J 26:4149–4159PubMed Sasabe J, Chiba T, Yamada M et al (2007) d-serine is a key determinant of glutamate toxicity in amyotrophic lateral sclerosis. EMBO J 26:4149–4159PubMed
91.
go back to reference Sasabe J, Miyoshi Y, Suzuki M et al (2012) d-amino acid oxidase controls motoneuron degeneration through d-serine. Proc Natl Acad Sci USA 109:627–632PubMed Sasabe J, Miyoshi Y, Suzuki M et al (2012) d-amino acid oxidase controls motoneuron degeneration through d-serine. Proc Natl Acad Sci USA 109:627–632PubMed
92.
go back to reference 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 107:7556–7561PubMed 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 107:7556–7561PubMed
93.
go back to reference 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 39:366–372PubMed 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 39:366–372PubMed
94.
go back to reference Orlacchio A, Babalini C, Borreca A et al (2010) SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis. Brain 133:591–598PubMed Orlacchio A, Babalini C, Borreca A et al (2010) SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis. Brain 133:591–598PubMed
95.
go back to reference 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 36:377–381PubMed 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 36:377–381PubMed
96.
go back to reference Johnson JO, Mandrioli J, Benatar M et al (2010) Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68:857–864PubMed Johnson JO, Mandrioli J, Benatar M et al (2010) Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68:857–864PubMed
97.
go back to reference Rohrer JD, Warren JD, Reiman D et al (2011) A novel exon 2 I27V VCP variant is associated with dissimilar clinical syndromes. J Neurol 258:1494–1496PubMed Rohrer JD, Warren JD, Reiman D et al (2011) A novel exon 2 I27V VCP variant is associated with dissimilar clinical syndromes. J Neurol 258:1494–1496PubMed
98.
go back to reference 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 66:152–157PubMed 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 66:152–157PubMed
99.
go back to reference Meyer H, Bug M, Bremer S (2012) Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system. Nat Cell Biol 14:117–123PubMed Meyer H, Bug M, Bremer S (2012) Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system. Nat Cell Biol 14:117–123PubMed
100.
go back to reference 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 187:875–888PubMed 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 187:875–888PubMed
101.
go back to reference 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 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.
go back to reference 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 19:1741–1755PubMed 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 19:1741–1755PubMed
103.
go back to reference 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:e374PubMed 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:e374PubMed
104.
go back to reference 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 477:211–215PubMed 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 477:211–215PubMed
105.
go back to reference Williams KL, Warraich ST, Yang S et al (2012) UBQLN2/ubiquilin 2 mutation and pathology in familial amyotrophic lateral sclerosis. Neurobiol Aging 33:2527 e2523–2510 Williams KL, Warraich ST, Yang S et al (2012) UBQLN2/ubiquilin 2 mutation and pathology in familial amyotrophic lateral sclerosis. Neurobiol Aging 33:2527 e2523–2510
106.
go back to reference Rothenberg C, Srinivasan D, Mah L et al (2010) Ubiquilin functions in autophagy and is degraded by chaperone-mediated autophagy. Hum Mol Genet 19:3219–3232PubMed Rothenberg C, Srinivasan D, Mah L et al (2010) Ubiquilin functions in autophagy and is degraded by chaperone-mediated autophagy. Hum Mol Genet 19:3219–3232PubMed
107.
go back to reference Lee DY, Brown EJ (2012) Ubiquilins in the crosstalk among proteolytic pathways. Biol Chem 393:441–447PubMed Lee DY, Brown EJ (2012) Ubiquilins in the crosstalk among proteolytic pathways. Biol Chem 393:441–447PubMed
108.
go back to reference 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 72:245–256PubMed 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 72:245–256PubMed
109.
go back to reference 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 72:257–268PubMed 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 72:257–268PubMed
110.
go back to reference 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 92:345–353PubMed 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 92:345–353PubMed
111.
go back to reference Cruts M, Gijselinck I, Van Langenhove T et al (2013) Current insights into the C9orf72 repeat expansion diseases of the FTLD/ALS spectrum. Trends Neurosci Cruts M, Gijselinck I, Van Langenhove T et al (2013) Current insights into the C9orf72 repeat expansion diseases of the FTLD/ALS spectrum. Trends Neurosci
112.
go back to reference 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 21:102–108PubMed 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 21:102–108PubMed
113.
go back to reference 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 11:323–330PubMed 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 11:323–330PubMed
114.
go back to reference 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.e2218 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.e2218
115.
go back to reference Ishiura H, Takahashi Y, Mitsui J et al (2012) C9ORF72 repeat expansion in amyotrophic lateral sclerosis in the Kii peninsula of Japan. Arch Neurol 69:1154–1158PubMed Ishiura H, Takahashi Y, Mitsui J et al (2012) C9ORF72 repeat expansion in amyotrophic lateral sclerosis in the Kii peninsula of Japan. Arch Neurol 69:1154–1158PubMed
116.
go back to reference 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–e2526 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–e2526
117.
go back to reference 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 84:398–401PubMed 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 84:398–401PubMed
118.
go back to reference 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–e1319 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–e1319
119.
go back to reference 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–e1716 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–e1716
120.
go back to reference 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 11:232–240PubMed 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 11:232–240PubMed
121.
go back to reference 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 259:1749–1751PubMed 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 259:1749–1751PubMed
122.
go back to reference 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 259:2723–2725PubMed 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 259:2723–2725PubMed
123.
go back to reference 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 122:691–702PubMed 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 122:691–702PubMed
124.
go back to reference 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 123:825–839PubMed 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 123:825–839PubMed
125.
go back to reference Mori K, Weng SM, Arzberger T et al (2013) The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339:1335–1338PubMed Mori K, Weng SM, Arzberger T et al (2013) The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339:1335–1338PubMed
126.
go back to reference Ash PE, Bieniek KF, Gendron TF et al (2013) Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 77:639–646PubMed Ash PE, Bieniek KF, Gendron TF et al (2013) Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 77:639–646PubMed
127.
go back to reference 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 29:499–503PubMed 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 29:499–503PubMed
128.
go back to reference 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 11:54–65PubMed 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 11:54–65PubMed
129.
go back to reference Wu CH, Fallini C, Ticozzi N et al (2012) Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 488:499–503PubMed Wu CH, Fallini C, Ticozzi N et al (2012) Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 488:499–503PubMed
130.
go back to reference 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–e1716 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–e1716
131.
go back to reference 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 Degener 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 Degener
132.
go back to reference 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 e1519–1510 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 e1519–1510
133.
go back to reference 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–e1702 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–e1702
134.
go back to reference 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–e1706 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–e1706
135.
go back to reference 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–e1715 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–e1715
136.
go back to reference Daoud H, Dobrzeniecka S, Camu W et al (2013) Mutation analysis of PFN1 in familial amyotrophic lateral sclerosis patients. Neurobiol Aging 34(1311):e1311–e1312 Daoud H, Dobrzeniecka S, Camu W et al (2013) Mutation analysis of PFN1 in familial amyotrophic lateral sclerosis patients. Neurobiol Aging 34(1311):e1311–e1312
137.
go back to reference 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–e1925 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–e1925
138.
go back to reference 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.e2210 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.e2210
139.
go back to reference Mockrin SC, Korn ED (1980) Acanthamoeba profilin interacts with G-actin to increase the rate of exchange of actin-bound adenosine 5′-triphosphate. Biochemistry 19:5359–5362PubMed Mockrin SC, Korn ED (1980) Acanthamoeba profilin interacts with G-actin to increase the rate of exchange of actin-bound adenosine 5′-triphosphate. Biochemistry 19:5359–5362PubMed
140.
go back to reference 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 22:291–299PubMed 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 22:291–299PubMed
141.
go back to reference Al-Saif A, Al-Mohanna F, Bohlega S (2011) A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis. Ann Neurol 70:913–919PubMed Al-Saif A, Al-Mohanna F, Bohlega S (2011) A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis. Ann Neurol 70:913–919PubMed
142.
go back to reference Hayashi T, Su TP (2007) Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell 131:596–610PubMed Hayashi T, Su TP (2007) Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell 131:596–610PubMed
143.
go back to reference 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 167:247–255PubMed 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 167:247–255PubMed
144.
go back to reference Katsuno M, Tanaka F, Sobue G (2012) Perspectives on molecular targeted therapies and clinical trials for neurodegenerative diseases. J Neurol Neurosurg Psychiatry 83:329–335PubMed Katsuno M, Tanaka F, Sobue G (2012) Perspectives on molecular targeted therapies and clinical trials for neurodegenerative diseases. J Neurol Neurosurg Psychiatry 83:329–335PubMed
145.
go back to reference Miller RG, Mitchell JD, Moore DH (2012) Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev 3:CD001447 Miller RG, Mitchell JD, Moore DH (2012) Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev 3:CD001447
146.
go back to reference 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 61:427–434PubMed 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 61:427–434PubMed
147.
go back to reference 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 113:535–542PubMed 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 113:535–542PubMed
148.
go back to reference Egawa N, Kitaoka S, Tsukita K et al (2012) Drug screening for ALS using patient-specific induced pluripotent stem cells. Sci Transl Med 4:145ra104 Egawa N, Kitaoka S, Tsukita K et al (2012) Drug screening for ALS using patient-specific induced pluripotent stem cells. Sci Transl Med 4:145ra104
149.
go back to reference Fecto F, Yan J, Vemula SP et al (2011) SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch Neurol 68:1440–1446PubMed Fecto F, Yan J, Vemula SP et al (2011) SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch Neurol 68:1440–1446PubMed
150.
go back to reference Sasaki S (2011) Autophagy in spinal cord motor neurons in sporadic amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 70:349–359PubMed Sasaki S (2011) Autophagy in spinal cord motor neurons in sporadic amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 70:349–359PubMed
151.
go back to reference 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 109:15024–15029PubMed 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 109:15024–15029PubMed
152.
go back to reference Anderson P, Kedersha N (2008) Stress granules: the Tao of RNA triage. Trends Biochem Sci 33:141–150PubMed Anderson P, Kedersha N (2008) Stress granules: the Tao of RNA triage. Trends Biochem Sci 33:141–150PubMed
153.
go back to reference Colombrita C, Zennaro E, Fallini C et al (2009) TDP-43 is recruited to stress granules in conditions of oxidative insult. J Neurochem 111:1051–1061PubMed Colombrita C, Zennaro E, Fallini C et al (2009) TDP-43 is recruited to stress granules in conditions of oxidative insult. J Neurochem 111:1051–1061PubMed
154.
go back to reference 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 9:37PubMed 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 9:37PubMed
155.
go back to reference 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 18:1385–1396PubMed 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 18:1385–1396PubMed
156.
go back to reference 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 285:608–619PubMed 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 285:608–619PubMed
157.
go back to reference Bosco DA, Lemay N, Ko HK et al (2010) Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules. Hum Mol Genet 19:4160–4175PubMed Bosco DA, Lemay N, Ko HK et al (2010) Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules. Hum Mol Genet 19:4160–4175PubMed
158.
go back to reference Dormann D, Rodde R, Edbauer D et al (2010) ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import. EMBO J 29:2841–2857PubMed Dormann D, Rodde R, Edbauer D et al (2010) ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import. EMBO J 29:2841–2857PubMed
159.
go back to reference 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:e13250PubMed 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:e13250PubMed
160.
go back to reference Nonaka T, Masuda-Suzukake M, Arai T et al (2013) Prion-like properties of pathological TDP-43 aggregates from diseased brains. Cell Rep 4:124–134PubMed Nonaka T, Masuda-Suzukake M, Arai T et al (2013) Prion-like properties of pathological TDP-43 aggregates from diseased brains. Cell Rep 4:124–134PubMed
161.
go back to reference Couthouis J, Hart MP, Shorter J et al (2011) A yeast functional screen predicts new candidate ALS disease genes. Proc Natl Acad Sci USA 108:20881–20890PubMed Couthouis J, Hart MP, Shorter J et al (2011) A yeast functional screen predicts new candidate ALS disease genes. Proc Natl Acad Sci USA 108:20881–20890PubMed
162.
go back to reference 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 21:2899–2911PubMed 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 21:2899–2911PubMed
163.
go back to reference Kim HJ, Kim NC, Wang YD et al (2013) Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495:467–473PubMed Kim HJ, Kim NC, Wang YD et al (2013) Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495:467–473PubMed
Metadata
Title
Amyotrophic lateral sclerosis: an update on recent genetic insights
Authors
Yohei Iguchi
Masahisa Katsuno
Kensuke Ikenaka
Shinsuke Ishigaki
Gen Sobue
Publication date
01-11-2013
Publisher
Springer Berlin Heidelberg
Published in
Journal of Neurology / Issue 11/2013
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI
https://doi.org/10.1007/s00415-013-7112-y

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