Mislocalization, aggregation formation and defect in proteolysis in ALS

Atsushi Tsubota; Hidenori Ichijo; Kengo Homma; Atsushi Tsubota; Hidenori Ichijo; Kengo Homma

doi:10.3934/molsci.2016.2.246

AIMS Molecular Science

2016, Volume 3, Issue 2: 246-268. doi: 10.3934/molsci.2016.2.246

Previous Article Next Article

Review Special Issues

Mislocalization, aggregation formation and defect in proteolysis in ALS

Laboratory of Cell Signaling, Graduate school of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan

Received: 20 March 2016 Accepted: 17 May 2016 Published: 25 January 2016

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motoneuron degeneration. The features observed in ALS are the mislocalization and aggregation of proteins in the affected motoneurons. The mutants of Cu/Zn superoxide dismutase (SOD1) or TAR DNA binding protein (TDP-43) that cause ALS have been reported to localize aberrantly. These aggregations contain the products of ALS causative genes, including SOD1 or TDP-43. Notably, TDP-43-positive aggregations have been identified even in sporadic ALS cases, indicating the importance of aggregate formation in the pathogenesis of ALS. Various proteins other than ALS causative gene products are also included in these aggregates. It is thought that the genetic mutation-induced conformational changes of proteins cause the aberrant redistribution and formation of aggregates, resulting in a loss of function or a gain of neuronal toxicity through the undesired interactions. Additionally, valosin-containing protein (VCP), ubiquilin2 (UBQLN2) and optineurin (OPTN), which are related to the proteolysis system, have also been identified as causative genes in ALS. These facts suggest that the aberrant protein homeostasis mediated by mislocalization, aggregate formation, or defects in the proteolysis system are the underlying causes of neuronal toxicity in ALS. Here, we focus on the impaired protein homeostasis observed in ALS to discuss the potential for motoneuron toxicity.
Citation: Atsushi Tsubota, Hidenori Ichijo, Kengo Homma. Mislocalization, aggregation formation and defect in proteolysis in ALS[J]. AIMS Molecular Science, 2016, 3(2): 246-268. doi: 10.3934/molsci.2016.2.246

Related Papers:

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motoneuron degeneration. The features observed in ALS are the mislocalization and aggregation of proteins in the affected motoneurons. The mutants of Cu/Zn superoxide dismutase (SOD1) or TAR DNA binding protein (TDP-43) that cause ALS have been reported to localize aberrantly. These aggregations contain the products of ALS causative genes, including SOD1 or TDP-43. Notably, TDP-43-positive aggregations have been identified even in sporadic ALS cases, indicating the importance of aggregate formation in the pathogenesis of ALS. Various proteins other than ALS causative gene products are also included in these aggregates. It is thought that the genetic mutation-induced conformational changes of proteins cause the aberrant redistribution and formation of aggregates, resulting in a loss of function or a gain of neuronal toxicity through the undesired interactions. Additionally, valosin-containing protein (VCP), ubiquilin2 (UBQLN2) and optineurin (OPTN), which are related to the proteolysis system, have also been identified as causative genes in ALS. These facts suggest that the aberrant protein homeostasis mediated by mislocalization, aggregate formation, or defects in the proteolysis system are the underlying causes of neuronal toxicity in ALS. Here, we focus on the impaired protein homeostasis observed in ALS to discuss the potential for motoneuron toxicity.

References

[1]	Rosen DR, Siddique T, Patterson D, et al. (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362: 59-62. doi: 10.1038/362059a0
[2]	Sreedharan J, Blair IP, Tripathi VB, et al. (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 249: 1668-1672.
[3]	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: 245-256. doi: 10.1016/j.neuron.2011.09.011
[4]	Renton AE, Majounie E, Waite A, et al. (2011) A Hexanucleotide repeat expansion in C9ORF72 is the aause of chromosome 9p21-linked ALS-FTD. Neuron 72: 257-268. doi: 10.1016/j.neuron.2011.09.010
[5]	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: 323-330. doi: 10.1016/S1474-4422(12)70043-1
[6]	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: 733-747. doi: 10.1007/s00401-012-1035-z
[7]	Neumann M, Sampathu DM, Kwong LK, et al. (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 130: 130-133.
[8]	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: 602-611. doi: 10.1016/j.bbrc.2006.10.093
[9]	Leigh PN, Anderton BH, Dodson A, et al. (1988) Ubiquitin deposits in anterior horn cells in motor neuron disease. Neurosci Lett 93: 197-203. doi: 10.1016/0304-3940(88)90081-X
[10]	Johnson JO, Mandrioli J, Benatar M, et al. (2010) Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68: 857-864. doi: 10.1016/j.neuron.2010.11.036
[11]	Deng H-X, Chen W, Hong S-T, et al. (2011) Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 477: 211-215. doi: 10.1038/nature10353
[12]	Maruyama H, Morino H, Ito H, et al. (2010) Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465: 223-226. doi: 10.1038/nature08971
[13]	ALSoD (Amyotrophic Lateral Sclerosis Online Genetics Database). Available from: http://alsod.iop.kcl.ac.uk/
[14]	Cleveland DW, Laing N, Hurse PV, et al. (1995) Toxic mutants in Charcot’s sclerosis. Nature 378: 342-343. doi: 10.1038/378342a0
[15]	Bruijn LI, Houseweart MK, Kato S, et al. (1998) Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1. Science 281: 1851-1854.
[16]	Hayward LJ, Rodriguez JA, Kim JW, et al. (2002) Decreased metallation and activity in subsets of mutant superoxide dismutases associated with familial amyotrophic lateral sclerosis. J Biol Chem 277: 15923-15931. doi: 10.1074/jbc.M112087200
[17]	Reaume AG, Elliott JL, Hoffman EK, et al. (1996) Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. Nat Genet 13: 43-47. doi: 10.1038/ng0596-43
[18]	Fujisawa T, Homma K, Yamaguchi N, et al. (2012) A novel monoclonal antibody reveals a conformational alteration shared by amyotrophic lateral sclerosis-linked SOD1 mutants. Ann Neurol 72: 739-49. doi: 10.1002/ana.23668
[19]	Urushitani M, Ezzi SA, Julien JP (2007) Therapeutic effects of immunization with mutant superoxide dismutase in mice models of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 104: 2495-2500. doi: 10.1073/pnas.0606201104
[20]	Bosco DA, Morfini G, Karabacak NM, et al. (2010) Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS. Nat Neurosci 13: 1396-1403. doi: 10.1038/nn.2660
[21]	Watanabe M, Dykes-Hoberg M, Culotta VC, et al. (2001) Histological evidence of protein aggregation in mutant SOD1 transgenic mice and in amyotrophic lateral sclerosis neural tissues. Neurobiol Dis 8: 933-941. doi: 10.1006/nbdi.2001.0443
[22]	Basso M, Massignan T, Samengo G, et al. (2006) Insoluble mutant SOD1 is partly oligoubiquitinated in amyotrophic lateral sclerosis mice. J Biol Chem 281: 33325-33335. doi: 10.1074/jbc.M603489200
[23]	Wang J, Xu G, Gonzales V, et al. (2002) Fibrillar inclusions and motor neuron degeneration in transgenic mice expressing superoxide dismutase 1 with a disrupted copper-binding site. Neurobiol Dis 10: 128-138. doi: 10.1006/nbdi.2002.0498
[24]	Furukawa Y, Fu R, Deng HX, et al. (2006) Disulfide cross-linked protein represents a significant fraction of ALS-associated Cu, Zn-superoxide dismutase aggregates in spinal cords of model mice. Proc Natl Acad Sci U S A 103: 7148-7153. doi: 10.1073/pnas.0602048103
[25]	Rodriguez JA, Valentine JS, Eggers DK, et al. (2002) Familial amyotrophic lateral sclerosis-associated mutations decrease the thermal stability of distinctly metallated species of human Copper/Zinc superoxide dismutase. J Biol Chem 277: 15932-15937. doi: 10.1074/jbc.M112088200
[26]	Sea K, Sohn SH, Durazo A, et al. (2015) Insights into the role of the unusual disulfide bond in Copper-Zinc superoxide dismutase. J Biol Chem 290: 2405-2418. doi: 10.1074/jbc.M114.588798
[27]	Doucette PA, Whitson LJ, Cao X, et al. (2004) Dissociation of human copper-zinc superoxide dismutase dimers using chaotrope and reductant: Insights into the molecular basis for dimer stability. J Biol Chem 279: 54558-54566. doi: 10.1074/jbc.M409744200
[28]	Hough MA, Grossmann JG, Antonyuk SV, et al. (2004) Dimer destabilization in superoxide dismutase may result in disease-causing properties: structures of motor neuron disease mutants. Proc Natl Acad Sci U S A 101: 5976-5981. doi: 10.1073/pnas.0305143101
[29]	Araki K, Iemura S, Kamiya Y, et al. (2013) Ero1-α and PDIs constitute a hierarchical electron transfer network of endoplasmic reticulum oxidoreductases. J Cell Biol 202: 861-874. doi: 10.1083/jcb.201303027
[30]	Atkin JD, Farg MA, Turner BJ, et al. (2006) Induction of the unfolded protein response in familial amyotrophic lateral sclerosis and association of protein-disulfide isomerase with superoxide dismutase 1. J Biol Chem 281: 30152-30165. doi: 10.1074/jbc.M603393200
[31]	Chen X, Zhang X, Li C, et al. (2013) S-nitrosylated protein disulfide isomerase contributes to mutant SOD1 aggregates in amyotrophic lateral sclerosis. J Neurochem 124: 45-58. doi: 10.1111/jnc.12046
[32]	Jeon GS, Nakamura T, Lee JS, et al. (2014) Potential effect of S-nitrosylated protein disulfide isomerase on mutant SOD1 aggregation and neuronal cell death in amyotrophic lateral sclerosis. Mol Neurobiol 49: 796-807. doi: 10.1007/s12035-013-8562-z
[33]	Honjo Y, Kaneko S, Ito H, et al. (2011) Protein disulfide isomerase-immunopositive inclusions in patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2968: 1-7.
[34]	Toichi K, Yamanaka K, Furukawa Y (2013) Disulfide scrambling describes the oligomer formation of superoxide dismutase (SOD1) proteins in the familial form of amyotrophic lateral sclerosis. J Biol Chem 288: 4970-4980. doi: 10.1074/jbc.M112.414235
[35]	Crow JP, Sampson JB, Zhuang Y, et al. (1997) Decreased zinc affinity of amyotrophic lateral sclerosis-associated superoxide dismutase mutants leads to enhanced catalysis of tyrosine nitration by peroxynitrite. J Neurochem 69: 1936-1944.
[36]	Lyons TJ, Liu H, Goto JJ, et al. (1996) Mutation in copper-zinc superoxide dismutase that cause amyotrophic lateral sclerosis alter the zinc binding site and the redox behavior of the protein. Proc Natl Acad Sci U S A 93: 12240-12244. doi: 10.1073/pnas.93.22.12240
[37]	Homma K, Fujisawa T, Tsuburaya N, et al. (2013) SOD1 as a molecular switch for initiating the homeostatic ER stress response under zinc deficiency. Mol Cell 52: 75-86. doi: 10.1016/j.molcel.2013.08.038
[38]	Urushitani M, Sik A, Sakurai T, et al. (2006) Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis. Nat Neurosci 9: 108-118. doi: 10.1038/nn1603
[39]	Israelson A, Ditsworth D, Sun S, et al. (2013) Macrophage migration inhibitory factor as a chaperone inhibiting accumulation of misfolded SOD1. Neuron 86: 218–232. doi: 10.1016/j.neuron.2015.02.034
[40]	Tan W, Naniche N, Bogush A, et al. (2013) Small peptides against the mutant SOD1/Bcl-2 toxic mitochondrial complex restore mitochondrial function and cell viability in mutant SOD1-mediated ALS. J Neurosci 33: 11588-11598. doi: 10.1523/JNEUROSCI.5385-12.2013
[41]	Kikuchi H, Almer G, Yamashita S, et al. (2006) Spinal cord endoplasmic reticulum stress associated with a microsomal accumulation of mutant superoxide dismutase-1 in an ALS model. Proc Natl Acad Sci U S A 103: 6025-6030. doi: 10.1073/pnas.0509227103
[42]	Sun S, Sun Y, Ling SC, et al. (2015) Translational profiling identifies a cascade of damage initiated in motor neurons and spreading to glia in mutant SOD1-mediated ALS. Proc Natl Acad Sci U S A 112: E6993-E7002. doi: 10.1073/pnas.1520639112
[43]	Ito Y, Yamada M, Tanaka H, et al. (2009) Involvement of CHOP, an ER-stress apoptotic mediator, in both human sporadic ALS and ALS model mice. Neurobiol Dis 36: 470-476. doi: 10.1016/j.nbd.2009.08.013
[44]	Nishitoh H, Kadowaki H, Nagai A, et al. (2008) ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1. Genes Dev 22: 1451-1464. doi: 10.1101/gad.1640108
[45]	Pokrishevsky E, Grad LI, Yousefi M, et al. (2012) Aberrant localization of FUS and TDP43 is associated with misfolding of SOD1 in amyotrophic lateral sclerosis. PLoS One 7: 1-9.
[46]	Dimos JT, Rodolfa KT, Niakan KK, et al. (2008) Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321: 1218-1221. doi: 10.1126/science.1158799
[47]	Chen H, Qian K, Du Z, et al. (2014) Modeling ALS with iPSCs reveals that mutant SOD1 misregulates neurofilament balance in motor neurons. Cell Stem Cell 14: 796-809. doi: 10.1016/j.stem.2014.02.004
[48]	Kiskinis E, Sandoe J, Williams LA, et al. (2014) Pathways disrupted in human ALS motor neurons identified through genetic correction of mutant SOD1. Cell Stem Cell 14: 781-795. doi: 10.1016/j.stem.2014.03.004
[49]	Neary D, Snowden JS, Mann DM (2000) Classification and description of frontotemporal dementias. Ann N Y Acad Sci 920: 46-51.
[50]	Higashi S, Iseki E, Yamamoto R, et al. (2007) Concurrence of TDP-43, tau and α-synuclein pathology in brains of Alzheimer’s disease and dementia with Lewy bodies. Brain Res 1184: 284-294. doi: 10.1016/j.brainres.2007.09.048
[51]	Ou SH, Wu F, Harrich D, et al. (1995) Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs. J Virol 69: 3584-3596.
[52]	Lu Y, Ferris J, Gao FB (2009) Frontotemporal dementia and amyotrophic lateral sclerosis-associated disease protein TDP-43 promotes dendritic branching. Mol Brain 2: 30. doi: 10.1186/1756-6606-2-30
[53]	Winton MJ, Igaz LM, Wong MM, et al. (2008) Disturbance of nuclear and cytoplasmic TAR DNA-binding protein (TDP-43) induces disease-like redistribution, sequestration, and aggregate formation. J Biol Chem 283: 13302-13309. doi: 10.1074/jbc.M800342200
[54]	Kuo PH, Doudeva LG, Wang YT, et al. (2009) Structural insights into TDP-43 in nucleic-acid binding and domain interactions. Nucleic Acids Res 37: 1799-1808. doi: 10.1093/nar/gkp013
[55]	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 exon9 splicing. J Biol Chem 280: 37572-37584. doi: 10.1074/jbc.M505557200
[56]	Kabashi E, Valdmanis PN, Dion P, et al. (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 40: 572-574. doi: 10.1038/ng.132
[57]	Johnson BS, McCaffery JM, Lindquist S, et al. (2008) A yeast TDP-43 proteinopathy model: Exploring the molecular determinants of TDP-43 aggregation and cellular toxicity. Proc Natl Acad Sci U S A 105: 6439-6444. doi: 10.1073/pnas.0802082105
[58]	Hasegawa M, Arai T, Nonaka T, et al. (2008) Phosphorylated TDP-43 in frontotemporal lobar degeneration and ALS. Ann Neurol 64: 60-70. doi: 10.1002/ana.21425
[59]	Kadokura A, Yamazaki T, Kakuda S, et al. (2009) Phosphorylation-dependent TDP-43 antibody detects intraneuronal dot-like structures showing morphological characters of granulovacuolar degeneration. Neurosci Lett 463: 87-92. doi: 10.1016/j.neulet.2009.06.024
[60]	Igaz LM, Kwong LK, Chen-Plotkin A, et al. (2009) Expression of TDP-43 C-terminal fragments in vitro recapitulates pathological features of TDP-43 proteinopathies. J Biol Chem 284: 8516-8524. doi: 10.1074/jbc.M809462200
[61]	Zhang YJ, Xu YF, Cook C, et al. (2009) Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity. Proc Natl Acad Sci U S A 106: 7607-7612. doi: 10.1073/pnas.0900688106
[62]	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: 602-611. doi: 10.1016/j.bbrc.2006.10.093
[63]	Dormann D, Capell A, Carlson AM, et al. (2009) Proteolytic processing of TAR DNA binding protein-43 by caspases produces C-terminal fragments with disease defining properties independent of progranulin. J Neurochem 110: 1082-1094. doi: 10.1111/j.1471-4159.2009.06211.x
[64]	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 U S A 107: 3858-3863. doi: 10.1073/pnas.0912417107
[65]	Giordana MT, Piccinini M, Grifoni S, et al. (2010) TDP-43 redistribution is an early event in sporadic amyotrophic lateral sclerosis. Brain Pathol 20: 351-360. doi: 10.1111/j.1750-3639.2009.00284.x
[66]	Udan M, Baloh RH (2011) Implications of the prion-related Q/N domains in TDP-43 and FUS. Prion 5: 1-5.
[67]	Nonaka T, Masuda-Suzukake M, Arai T, et al. (2013) Prion-like properties of pathological TDP-43 aggregates from diseased brains. Cell Rep 4: 124-134. doi: 10.1016/j.celrep.2013.06.007
[68]	Walker AK, Soo KY, Sundaramoorthy V, et al. (2013) ALS-associated TDP-43 induces endoplasmic reticulum stress, which drives cytoplasmic TDP-43 accumulation and stress granule formation. PLoS One 8: e81170. doi: 10.1371/journal.pone.0081170
[69]	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: 459-468. doi: 10.1038/nn.2779
[70]	Watanabe S, Kaneko K, Yamanaka K (2013) Accelerated disease onset with stabilized familial amyotrophic lateral ssclerosis (ALS)-linked mutant TDP-43 proteins. J Biol Chem 288: 3641-3654. doi: 10.1074/jbc.M112.433615
[71]	Iguchi Y, Katsuno M, Niwa J, et al. (2013) Loss of TDP-43 causes age-dependent progressive motor neuron degeneration. Brain 136: 1371-1382. doi: 10.1093/brain/awt029
[72]	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 U S A 106: 18809-18814. doi: 10.1073/pnas.0908767106
[73]	Feiguin F, Godena VK, Romano G, et al. (2009) Depletion of TDP-43 affects Drosophila motoneurons terminal synapsis and locomotive behavior. FEBS Lett 583: 1586-1592. doi: 10.1016/j.febslet.2009.04.019
[74]	Alami NH, Smith RB, Carrasco MA, et al. (2013) Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations. Neuron 81: 536-543.
[75]	Xia Q, Wang H, Hao Z, et al. (2015) TDP-43 loss of function increases TFEB activity and blocks autophagosome-lysosome fusion. EMBO J 35: 1-22.
[76]	Armakola M, Higgins MJ, Figley MD, et al. (2012) Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models. Nat Genet 44: 1302-1309. doi: 10.1038/ng.2434
[77]	Elden AC, Kim HJ, Hart MP, et al. (2010) Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466: 1069-1075. doi: 10.1038/nature09320
[78]	Liu-Yesucevitz L, Lin AY, Ebata A, et al. (2014) ALS-linked mutations enlarge TDP-43-enriched neuronal RNA granules in the dendritic arbor. J Neurosci 34: 4167-4174. doi: 10.1523/JNEUROSCI.2350-13.2014
[79]	Crozat A, Aman P, Mandahl N, et al. (1993) Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma. Nature 363: 640-644. doi: 10.1038/363640a0
[80]	Rabbits TH, Forster A, Larson R, et al. (1993) Fusion of the dominant negative transcription regulator CHOP with a novel gene FUS by translocation t (12; 16) in malignant liposarcoma. Nat Genet 4: 175-180. doi: 10.1038/ng0693-175
[81]	Vance C, Rogelj B, Hortobágyi T, et al. (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis Type 6. Science 323: 1208-1211. doi: 10.1126/science.1165942
[82]	Kwiatkowski TJ, Bosco DA, Leclerc AL, et al. (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323: 1205-1208. doi: 10.1126/science.1166066
[83]	Neumann M, Rademakers R, Roeber S, et al. (2009) A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 132: 2922-2931. doi: 10.1093/brain/awp214
[84]	Kovar H (2011) The two faces of the FUS/EWS/TAF15 protein family. Sarcoma 2011: 1-13.
[85]	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: 2899-2911. doi: 10.1093/hmg/dds116
[86]	Lee BJ, Cansizoglu AE, Süel KE, et al. (2006) Rules for Nuclear Localization Sequence Recognition by Karyopherinβ2. Cell 126: 543-558. doi: 10.1016/j.cell.2006.05.049
[87]	Dormann D, Rodde R, Edbauer D, et al. (2010) ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import. EMBO J 29: 2841-2857. doi: 10.1038/emboj.2010.143
[88]	Dormann D, Madl T, Valori CF, et al. (2012) Arginine methylation next to the PY-NLS modulates Transportin binding and nuclear import of FUS. EMBO J 31: 4258-4275. doi: 10.1038/emboj.2012.261
[89]	Snowden JS, Hu Q, Rollinson S, et al. (2011) The most common type of FTLD-FUS (aFTLD-U) is associated with a distinct clinical form of frontotemporal dementia but is not related to mutations in the FUS gene. Acta Neuropathol 122: 99-110. doi: 10.1007/s00401-011-0816-0
[90]	Urwin H, Josephs KA, Rohrer JD, et al. (2010) FUS pathology defines the majority of tau-and TDP-43-negative frontotemporal lobar degeneration. Acta Neuropathol 120: 33-41. doi: 10.1007/s00401-010-0698-6
[91]	Brelstaff J, Lashley T, Holton JL, et al. (2011) Transportin1: a marker of FTLD-FUS. Acta Neuropathol 122: 591-600. doi: 10.1007/s00401-011-0863-6
[92]	Davidson YS, Robinson AC, Hu Q, et al. (2013) Nuclear carrier and RNA-binding proteins in frontotemporal lobar degeneration associated with fused in sarcoma (FUS) pathological changes. Neuropathol Appl Neurobiol 39: 157-165. doi: 10.1111/j.1365-2990.2012.01274.x
[93]	Kuroda M, Sok J, Webb L, et al. (2000) Male sterility and enhanced radiation sensitivity in TLS(-/-) mice. EMBO J 19: 453-462. doi: 10.1093/emboj/19.3.453
[94]	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: 175-179. doi: 10.1038/72842
[95]	Kabashi E, Bercier V, Lissouba A, et al. (2011) FUS and TARDBP but not SOD1 interact in genetic models of amyotrophic lateral sclerosis. PLoS Genet 7: e1002214. doi: 10.1371/journal.pgen.1002214
[96]	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: 273-288. doi: 10.1007/s00401-012-1043-z
[97]	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: 499-503. doi: 10.1093/bioinformatics/bts725
[98]	Farg MA, Sundaramoorthy V, Sultana JM, et al. (2014) C9ORF72, implicated in amytrophic lateral sclerosis and frontemporal dementia, regulates endosomal trafficking. Hum Mol Genet 23: 3579-3595. doi: 10.1093/hmg/ddu068
[99]	Donnelly CJ, Zhang PW, Pham JT, et al. (2013) RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron 80: 415-428. doi: 10.1016/j.neuron.2013.10.015
[100]	Therrien M, Rouleau GA, Dion PA, et al. (2013) Deletion of C9ORF72 results in motor neuron degeneration and stress sensitivity in C. elegans. PLoS One 8: 1-10. doi: 10.1371/journal.pone.0083450
[101]	Ciura S, Lattante S, Le Ber I, et al. (2013) Loss of function of C9orf72 causes motor deficits in a zebrafish model of amyotrophic lateral sclerosis. Ann Neurol 74: 180-187.
[102]	Koppers M, Blokhuis AM, Westeneng H-J, et al. (2015) C9orf72 ablation in mice does not cause motor neuron degenerateon or motor deficit. Ann Neurol 78: 426-438. doi: 10.1002/ana.24453
[103]	Ranum LPW, Cooper TA (2006) RNA-mediated neuromascular disorders. Annu Rev Neurosci 29: 259-77.
[104]	Xu Z, Poidevin M, Li X, et al. (2013) Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration. Proc Natl Acad Sci U S A 110: 7778-7783. doi: 10.1073/pnas.1219643110
[105]	Haeusler AR, Donnelly CJ, Periz G, et al. (2014) C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature 507: 195-200.
[106]	Zu T, Gibbens B, Doty NS, et al. (2010) Non-ATG-initiated translation directed by microsatellite expansions. Proc Natl Acad Sci U S A 108: 260-265.
[107]	Mori K, Weng S, Arzberger T, et al. (2013) The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339: 1335-1339. doi: 10.1126/science.1232927
[108]	Mori K, Lammich S, Mackenzie IR, et al. (2013) hnRNP A3 bind to GGGGCC repeats and is a constituent of p62-positive/TDP-43-negative inclusions in the hippocampus of patients with C9orf72 mutations. Acta. Neuropathol 125: 413-423. doi: 10.1007/s00401-013-1088-7
[109]	Ash PEA, Bieniek KF, Gendron TF, et al. (2013) Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron 77: 639-646. doi: 10.1016/j.neuron.2013.02.004
[110]	Zhang YJ, Jansen-West K, Xu YF, et al. (2014) Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress. Acta Neuropathol 128: 505-524. doi: 10.1007/s00401-014-1336-5
[111]	Mizielinska S, Grönke S, Niccoli T, et al. (2014) C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science 345: 1192-1195. doi: 10.1126/science.1256800
[112]	Tran H, Almeida S, Moore J, et al. (2015) Differential toxicity of nuclear RNA foci versus dipeptide repeat proteins in a Drosophila model of C9ORF72 FTD/ALS. Neuron 87: 1207-1214 doi: 10.1016/j.neuron.2015.09.015
[113]	Chew J, Gendron TF, Prudencio M, et al. (2015) C9ORF72 repeat expansion in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits. Science 348: 2-6.
[114]	O’Rourke JG, Bogdanik L, Muhammad AKMG, et al. (2015) C9orf72 BAC Transgenic Mice Display Typical Pathologic Features of ALS/FTD. Neuron 88: 892-901. doi: 10.1016/j.neuron.2015.10.027
[115]	Zhang K, Donnelly CJ, Haeusler AR, et al. (2015) The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525: 56-61. doi: 10.1038/nature14973
[116]	Freibaum BD, Lu Y, Lopez-gonzalez R, et al. (2015) GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature 525: 129-133. doi: 10.1038/nature14974
[117]	Jovičić A, Mertens J, Boeynaems S, et al. (2015) Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nat Neurosci 18: 1226-1229. doi: 10.1038/nn.4085
[118]	Rezaie T, Child A, Hitchings R, et al. (2002) Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science 295: 1077-1079. doi: 10.1126/science.1066901
[119]	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: 1438-1443. doi: 10.1016/j.cub.2007.07.041
[120]	Wild P, Farhan H, McEwan DG, et al. (2011) Phosphorylation of the autophagy receptor Optineurin restricts salmonella growth. Science 333: 228-233.
[121]	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: 285-295. doi: 10.1083/jcb.200501162
[122]	Wild P, Farhan H, McEwan DG, et al. (2011) Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth. Science 333: 228-233. doi: 10.1126/science.1205405
[123]	Deng HX, Bigio EH, Zhai H, et al. (2012) Differential involvement of Optineurin in amyotrophic lateral sclerosis with or without SOD1 mutations. Arch Neurol 68: 1057-1061.
[124]	Ito H, Fujita K, Nakamura M, et al. (2011) Optineurin is co-localized with FUS in basophilic inclusions of ALS with FUS mutation and in basophilic inclusion body disease. Acta Neuropathol 121: 555-557. doi: 10.1007/s00401-011-0809-z
[125]	Williams KL, Warraich ST, Yang S, et al. (2012) UBQLN2/ubiquilin 2 mutation and pathology in familial amyotrophic lateral sclerosis. Neurobiol Aging 33: 2527.e3-10.
[126]	Seok Ko H, Uehara T, Tsuruma K, et al. (2004) Ubiquilin interacts with ubiquitylated proteins and proteasome through its ubiquitin-associated and ubiquitin-like domains. FEBS Lett 566: 110-114. doi: 10.1016/j.febslet.2004.04.031
[127]	Ritson GP, Custer SK, Freibaum BD, et al. (2010) TDP-43 mediates degeneration in a novel Drosophila model of disease caused by mutations in VCP/p97. J Neurosci 30: 7729-7739. doi: 10.1523/JNEUROSCI.5894-09.2010
[128]	Ye Y, Shibata Y, Yun C, et al. (2004) A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol. Nature 429: 841-847. doi: 10.1038/nature02656
[129]	Ye Y, Shibata Y, Kikkert M, et al. (2005) Recruitment of the p97 ATPase and ubiquitin ligases to the site of retrotranslocation at the endoplasmic reticulum membrane. Proc Natl Acad Sci U S A 102: 14132-14138. doi: 10.1073/pnas.0505006102
[130]	Song C, Wang Q, Li CH (2003) ATPase Activity of p97-Valosin-containing Protein (VCP). D2 mediates the major enzyme activity, and D1 contributes to the heat-induced activity. J Biol Chem 278: 3648-3655. doi: 10.1074/jbc.M208422200
[131]	Carvalho P, Stanley AM, Rapoport TA (2010) Retrotranslocation of a misfolded luminal ER protein by the ubiquitin-ligase Hrd1p. Cell 143: 579-591. doi: 10.1016/j.cell.2010.10.028
[132]	Bilican B, Serio A, Barmada SJ, et al. (2012) Mutant induced plu- ripotent stem cell lines recapitulate aspects of TDP-43 proteinopathies and reveal cell-specific vulnerability. Proc Natl Acad Sci U S A 109: 5803-5808. doi: 10.1073/pnas.1202922109
[133]	Liu X, Chen J, Liu W, et al. (2015) The fused in sarcoma protein forms cytoplasmic aggregates in motor neurons derived from integration-free induced pluripotent stem cells generated from a patient with familial amyotrophic lateral sclerosis carrying the FUS-P525L mutation. Neurogenetics 16: 223-231. doi: 10.1007/s10048-015-0448-y
[134]	Mackenzie IR, Bigio EH, Ince PG, et al. (2007) Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol 61: 427-434. doi: 10.1002/ana.21147
[135]	Yamanaka K, Chun SJ, Boillee S, et al. (2008) Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat Neurosci 11: 251-253. doi: 10.1038/nn2047

Reader Comments

Your name:*

Email:*
© 2016 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)