1,486
Views
0
CrossRef citations to date
0
Altmetric
Review

Multiple ways to a dead end: diverse mechanisms by which ALS mutant genes induce cell death

&
Pages 631-646 | Received 08 Dec 2020, Accepted 12 Jan 2021, Published online: 15 Mar 2021

References

  • Brooks BR, Miller RG, Swash M, et al. El escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Sci. 2000;1:293–299.
  • Brotman RG, Moreno-Escobar MC, Joseph J, et al. Amyotrophic lateral sclerosis. In: StatPearls. Treasure Island (FL): StatPearls Publishing; June 12, 2020.
  • Hardiman O, Al-Chalabi A, Chio A, et al. Amyotrophic lateral sclerosis. Nat Rev Dis Primers. 2017;3(1):17085.
  • Valko K, Ciesla L. Amyotrophic lateral sclerosis. Prog Med Chem. 2019;58:63–117.
  • Mitchell JD, Borasio GD. Amyotrophic lateral sclerosis. Lancet. 2007;369(9578):2031–2041.
  • Niedermeyer S, Murn M, Choi PJ. Respiratory failure in amyotrophic lateral sclerosis. Chest. 2019;155(2):401–408.
  • Laferriere F, Polymenidou M. Advances and challenges in understanding the multifaceted pathogenesis of amyotrophic lateral sclerosis. Swiss Med Wkly. 2015;145:w14054.
  • Alsultan AA, Waller R, Heath PR, et al. The genetics of amyotrophic lateral sclerosis: current insights. Degener Neurol Neuromuscul Dis. 2016;6:49–64.
  • Fay MM, Anderson PJ, Ivanov P. ALS/FTD-associated C9ORF72 repeat RNA promotes phase transitions in vitro and in cells. Cell Rep. 2017;21(12):3573–3584.
  • Gopal PP, Nirschl JJ, Klinman E, et al. Amyotrophic lateral sclerosis-linked mutations increase the viscosity of liquid-like TDP-43 RNP granules in neurons. Proc Natl Acad Sci U S A. 2017;114(12):E2466–E2475.
  • Johnson BS, Snead D, Lee JJ, et al. TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity. J Biol Chem. 2009;284(30):20329–20339.
  • Patel A, Lee HO, Jawerth L, et al. A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell. 2015;162(5):1066–1077.
  • Carija A, Navarro S, De Groot NS, et al. Protein aggregation into insoluble deposits protects from oxidative stress. Redox Biol. 2017;12:699–711.
  • Gill C, Phelan JP, Hatzipetros T et al SOD1-positive aggregate accumulation in the CNS predicts slower disease progression and increased longevity in a mutant SOD1 mouse model of ALS. Sci Rep 2019;9(1):6724.
  • Zhu C, Beck MV, Griffith JD, et al. Large SOD1 aggregates, unlike trimeric SOD1, do not impact cell viability in a model of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2018;115(18):4661–4665.
  • Cozzolino M, Pesaresi MG, Amori I, et al. Oligomerization of mutant SOD1 in mitochondria of motoneuronal cells drives mitochondrial damage and cell toxicity. Antioxid Redox Signal. 2009;11(7):1547–1558.
  • Kamelgarn M, Chen J, Kuang L, et al. ALS mutations of FUS suppress protein translation and disrupt the regulation of nonsense-mediated decay. Proc Natl Acad Sci U S A. 2018;115(51):E11904–E11913.
  • Mandrioli J, Mediani L, Alberti S, et al. ALS and FTD: where RNA metabolism meets protein quality control. Semin Cell Dev Biol. 2020;99:183–192.
  • Pasinelli P, Belford ME, Lennon N, et al. Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria. Neuron. 2004;43(1):19–30.
  • Woerner AC, Frottin F, Hornburg D, et al. Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA. Science. 2016a;351(6269):173–176. .
  • Soo KY, Sultana J, King AE, et al. ALS-associated mutant FUS inhibits macroautophagy which is restored by overexpression of Rab1. Cell Death Discov. 2015;1(1):15030.
  • Stoica R, Paillusson S, Gomez-Suaga P, et al. ALS/FTD-associated FUS activates GSK-3beta to disrupt the VAPB-PTPIP51 interaction and ER-mitochondria associations. EMBO Rep. 2016;17(9):1326–1342. .
  • Veglianese P, Lo Coco D, Bao Cutrona M, et al. Activation of the p38MAPK cascade is associated with upregulation of TNF alpha receptors in the spinal motor neurons of mouse models of familial ALS. Mol Cell Neurosci. 2006;31(2):218–231.
  • Guerrero EN, Mitra J, Wang H, et al. Amyotrophic lateral sclerosis-associated TDP-43 mutation Q331K prevents nuclear translocation of XRCC4-DNA ligase 4 complex and is linked to genome damage-mediated neuronal apoptosis. Hum Mol Genet. 2019;28(15):2459–2476.
  • Wang H, Guo W, Mitra J, et al. Mutant FUS causes DNA ligation defects to inhibit oxidative damage repair in amyotrophic lateral sclerosis. Nat Commun. 2018a;9(1):3683.
  • Wang WY, Pan L, Su SC, et al. Interaction of FUS and HDAC1 regulates DNA damage response and repair in neurons. Nat Neurosci. 2013b;16(10):1383–1391.
  • Balendra R, Isaacs AM. C9orf72-mediated ALS and FTD: multiple pathways to disease. Nat Rev Neurol. 2018;14(9):544–558.
  • Conlon EG, Manley JL. RNA-binding proteins in neurodegeneration: mechanisms in aggregate. Genes Dev. 2017;31(15):1509–1528.
  • Kim G, Gautier O, Tassoni-Tsuchida E, et al. ALS genetics: gains, losses, and implications for future therapies. Neuron. 2020;108(5):822–842.
  • Ling SC, Polymenidou M, Cleveland DW. Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron. 2013;79:416–438.
  • Taylor JP, Brown RH Jr., Cleveland DW. Decoding ALS: from genes to mechanism. Nature. 2016;539(7628):197–206.
  • Shorter J, Taylor JP. Disease mutations in the prion-like domains of hnRNPA1 and hnRNPA2/B1 introduce potent steric zippers that drive excess RNP granule assembly. Rare Dis. 2013;1(1):e25200.
  • Maharana S, Wang J, Papadopoulos DK, et al. RNA buffers the phase separation behavior of prion-like RNA binding proteins. Science. 2018;360(6391):918–921. .
  • Dormann D, Rodde R, Edbauer D, et al. ALS-associated fused in sarcoma (FUS) mutations disrupt transportin-mediated nuclear import. Embo J. 2010;29(16):2841–2857. .
  • Hofweber M, Hutten S, Bourgeois B, et al. Phase separation of FUS is suppressed by its nuclear import receptor and arginine methylation. Cell. 2018;173(3):706–719 e713. .
  • Yoshizawa T, Ali R, Jiou J, et al. Nuclear import receptor inhibits phase separation of FUS through binding to multiple sites. Cell. 2018;173(3):693–705 e622. .
  • Ito D, Seki M, Tsunoda Y, et al. Nuclear transport impairment of amyotrophic lateral sclerosis-linked mutations in FUS/TLS. Ann Neurol. 2011;69(1):152–162.
  • Chen X, Wu X, Wu H, et al. Phase separation at the synapse. Nat Neurosci. 2020;23(3):301–310.
  • Guillen-Boixet J, Kopach A, Holehouse AS, et al. RNA-induced conformational switching and clustering of G3BP drive stress granule assembly by condensation. Cell. 2020;181(2):346–361 e317. .
  • Hubstenberger A, Noble SL, Cameron C, et al. Translation repressors, an RNA helicase, and developmental cues control RNP phase transitions during early development. Dev Cell. 2013;27(2):161–173.
  • Takahara T, Maeda T. Transient sequestration of TORC1 into stress granules during heat stress. Mol Cell. 2012;47(2):242–252.
  • Wang Y, Hu SB, Wang MR, et al. Genome-wide screening of NEAT1 regulators reveals cross-regulation between paraspeckles and mitochondria. Nat Cell Biol. 2018b;20(10):1145–1158.
  • Mollet S, Cougot N, Wilczynska A, et al. Translationally repressed mRNA transiently cycles through stress granules during stress. Mol Biol Cell. 2008;19(10):4469–4479.
  • Zhang J, Okabe K, Tani T, et al. Dynamic association-dissociation and harboring of endogenous mRNAs in stress granules. J Cell Sci. 2011;124(23):4087–4095.
  • Mahboubi H, Stochaj U. Cytoplasmic stress granules: dynamic modulators of cell signaling and disease. Biochim Biophys Acta Mol Basis Dis. 2017;1863(4):884–895.
  • Wolozin B, Ivanov P. Stress granules and neurodegeneration. Nat Rev Neurosci. 2019;20(11):649–666.
  • Bom APDA, Rangel LP, Costa DCF, et al. Mutant p53 aggregates into prion-like amyloid oligomers and fibrils IMPLICATIONS FOR CANCER. J Biol Chem. 2012;287(33):28152–28162.
  • Wolozin B. Regulated protein aggregation: stress granules and neurodegeneration. Mol Neurodegener. 2012;7(1):56.
  • Conlon EG, Lu L, Sharma A, et al. The C9ORF72 GGGGCC expansion forms RNA G-quadruplex inclusions and sequesters hnRNP H to disrupt splicing in ALS brains. Elife. 2016;5. DOI:10.7554/eLife.17820
  • Hayes LR, Duan L, Bowen K, et al. C9orf72 arginine-rich dipeptide repeat proteins disrupt karyopherin-mediated nuclear import. Elife. 2020;9. DOI:10.7554/eLife.51685
  • Lee YB, Chen HJ, Peres JN, et al. Hexanucleotide repeats in ALS/FTD form length-dependent RNA foci, sequester RNA binding proteins, and are neurotoxic. Cell Rep. 2013;5(5):1178–1186. .
  • Mori K, Weng SM, Arzberger T, et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science. 2013;339(6125):1335–1338. .
  • Zhang K, Donnelly CJ, Haeusler AR, et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature. 2015;525(7567):56–61. .
  • Cruts M, Gijselinck I, Van Langenhove T, et al. Current insights into the C9orf72 repeat expansion diseases of the FTLD/ALS spectrum. Trends Neurosci. 2013;36(8):450–459.
  • Prado LGR, Bicalho ICS, Magalhaes D, et al. C9ORF72 and the FTD-ALS spectrum: a systematic review of neuroimaging studies. Dement Neuropsychol. 2015;9(4):413–421.
  • Chou CC, Zhang Y, Umoh ME, et al. TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD. Nat Neurosci. 2018;21(2):228–239. .
  • Hoell JI, Larsson E, Runge S, et al. RNA targets of wild-type and mutant FET family proteins. Nat Struct Mol Biol. 2011;18(12):1428–1431.
  • Baralle FE, Giudice J. Alternative splicing as a regulator of development and tissue identity. Nat Rev Mol Cell Biol. 2017;18(7):437–451.
  • Prudencio M, Belzil VV, Batra R, et al. Distinct brain transcriptome profiles in C9orf72-associated and sporadic ALS. Nat Neurosci. 2015;18(8):1175–1182. .
  • Sun S, Ling SC, Qiu J, et al. ALS-causative mutations in FUS/TLS confer gain and loss of function by altered association with SMN and U1-snRNP. Nat Commun. 2015;6(1):6171. .
  • Umoh ME, Fournier C, Li Y, et al. Comparative analysis of C9orf72 and sporadic disease in an ALS clinic population. Neurology. 2016;87(10):1024–1030.
  • Wang Q, Conlon EG, Manley JL, et al. Widespread intron retention impairs protein homeostasis in C9orf72 ALS brains. Genome Res. 2020;30(12):1705–1715.
  • Conlon EG, Fagegaltier D, Agius P,,, et al. Unexpected similarities between C9ORF72 and sporadic forms of ALS/FTD suggest a common disease mechanism. Elife. 2018;7. 10.7554/eLife.37754
  • Reber S, Stettler J, Filosa G, et al. Minor intron splicing is regulated by FUS and affected by ALS-associated FUS mutants. Embo J. 2016;35(14):1504–1521. .
  • Gerbino V, Carri MT, Cozzolino M, et al. Mislocalised FUS mutants stall spliceosomal snRNPs in the cytoplasm. Neurobiol Dis. 2013;55:120–128.
  • Ling JP, Pletnikova O, Troncoso JC, Wong PC. TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD. Science. 2015;349(6248):650–625.
  • Tian B, Manley JL. Alternative polyadenylation of mRNA precursors. Nat Rev Mol Cell Biol. 2017;18(1):18–30.
  • Li WC, You B, Hoque M, et al. Systematic profiling of poly(A) plus transcripts modulated by core 3 ‘ end processing and splicing factors reveals regulatory rules of alternative cleavage and polyadenylation. PLoS Genet. 2015;11(4):e1005166.
  • Nazim M, Masuda A, Rahman MA, et al. Competitive regulation of alternative splicing and alternative polyadenylation by hnRNP H and CstF64 determines acetylcholinesterase isoforms. Nucleic Acids Res. 2017;45(3):1455–1468.
  • Masuda A, Takeda J, Okuno T, et al. Position-specific binding of FUS to nascent RNA regulates mRNA length. Genes Dev. 2015;29(10):1045–1057.
  • Rot G, Wang Z, Huppertz I, et al. High-resolution RNA maps suggest common principles of splicing and polyadenylation regulation by TDP-43. Cell Rep. 2017;19(5):1056–1067.
  • Tian B, Manley JL. Alternative cleavage and polyadenylation: the long and short of it. Trends Biochem Sci. 2013;38(6):312–320.
  • Tank EM, Figueroa-Romero C, Hinder LM, et al. Abnormal RNA stability in amyotrophic lateral sclerosis. Nat Commun. 2018;9(1):2845.
  • Zhou Y, Liu S, Liu G, et al. ALS-associated FUS mutations result in compromised FUS alternative splicing and autoregulation. PLoS Genet. 2013;9(10):e1003895.
  • Avendano-Vazquez SE, Dhir A, Bembich S, et al. Autoregulation of TDP-43 mRNA levels involves interplay between transcription, splicing, and alternative polyA site selection. Genes Dev. 2012;26(15):1679–1684.
  • Mitchell JC, McGoldrick P, Vance C, et al. Overexpression of human wild-type FUS causes progressive motor neuron degeneration in an age- and dose-dependent fashion. Acta Neuropathol. 2013;125(2):273–288.
  • Wils H, Kleinberger G, Janssens J, et al. TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci U S A. 2010;107(8):3858–3863.
  • Chang YF, Imam JS, Wilkinson MF. The nonsense-mediated decay RNA surveillance pathway. Annu Rev Biochem. 2007;76(1):51–74.
  • Ortega JA, Daley EL, Kour S, et al. Nucleocytoplasmic proteomic analysis uncovers eRF1 and nonsense-mediated decay as modifiers of ALS/FTD C9orf72 toxicity. Neuron. 2020;106(1):90–107 e113.
  • Sun Y, Eshov A, Zhou J, et al. C9orf72 arginine-rich dipeptide repeats inhibit UPF1-mediated RNA decay via translational repression. Nat Commun. 2020;11(1):3354.
  • Xu W, Bao P, Jiang X, et al. Reactivation of nonsense-mediated mRNA decay protects against C9orf72 dipeptide-repeat neurotoxicity. Brain. 2019;142(5):1349–1364.
  • Barmada SJ, Ju S, Arjun A, et al. Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1. Proc Natl Acad Sci U S A. 2015;112(25):7821–7826.
  • Isken O, Kim YK, Hosoda N, et al. Upf1 phosphorylation triggers translational repression during nonsense-mediated mRNA decay. Cell. 2008;133(2):314–327.
  • Smith EF, Shaw PJ, De Vos KJ. The role of mitochondria in amyotrophic lateral sclerosis. Neurosci Lett. 2019;710:132933.
  • Deng J, Yang M, Chen Y, et al. FUS interacts with HSP60 to promote mitochondrial damage. PLoS Genet. 2015;11(9):e1005357.
  • Onesto E, Colombrita C, Gumina V, et al. Gene-specific mitochondria dysfunctions in human TARDBP and C9ORF72 fibroblasts. Acta Neuropathol Commun. 2016;4(1):47.
  • Deng J, Wang P, Chen X, et al. FUS interacts with ATP synthase beta subunit and induces mitochondrial unfolded protein response in cellular and animal models. Proc Natl Acad Sci U S A. 2018;115(41):E9678–E9686.
  • Wang W, Li L, Lin WL, et al. The ALS disease-associated mutant TDP-43 impairs mitochondrial dynamics and function in motor neurons. Hum Mol Genet. 2013a;22(23):4706–4719.
  • Nakaya T, Maragkakis M. Amyotrophic lateral sclerosis associated FUS mutation shortens mitochondria and induces neurotoxicity. Sci Rep. 2018;8(1):15575.
  • Tsai Y-L, Coady TH, Lu L, et al. ALS/FTD-associated protein FUS induces mitochondrial dysfunction by preferentially sequestering respiratory chain complex mRNAs. Genes Dev. 2020;34(11–12):785–805.
  • Wang W, Wang L, Lu J, et al. The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity. Nat Med. 2016;22(8):869–878.
  • Wang P, Deng J, Dong J, et al. TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response. PLoS Genet. 2019;15(5):e1007947.
  • Shpilka T, Haynes CM. The mitochondrial UPR: mechanisms, physiological functions and implications in ageing. Nat Rev Mol Cell Biol. 2018;19(2):109–120.
  • Martinez BA, Petersen DA, Gaeta AL, et al. Dysregulation of the mitochondrial unfolded protein response induces non-apoptotic dopaminergic neurodegeneration in C. elegans models of parkinson’s disease. J Neurosci. 2017;37(46):11085–11100.
  • Rizzuto R, Pinton P, Carrington W, et al. Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca2+ responses. Science. 1998;280(5370):1763–1766.
  • Kornmann B. The molecular hug between the ER and the mitochondria. Curr Opin Cell Biol. 2013;25(4):443–448.
  • Rowland AA, Voeltz GK. Endoplasmic reticulum-mitochondria contacts: function of the junction. Nat Rev Mol Cell Biol. 2012;13(10):607–625.
  • Saotome M, Safiulina D, Szabadkai G, et al. Bidirectional Ca2+-dependent control of mitochondrial dynamics by the miro GTPase. Proc Natl Acad Sci U S A. 2008;105(52):20728–20733.
  • Stoica R, De Vos KJ, Paillusson S, et al. ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43. Nat Commun. 2014;5(1):3996. .
  • Zhang YJ, Gendron TF, Grima JC, et al. C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins. Nat Neurosci. 2016;19(5):668–677.
  • Bischoff FR, Klebe C, Kretschmer J, et al. RanGAP1 induces GTPase activity of nuclear ras-related ran. Proc Natl Acad Sci U S A. 1994;91(7):2587–2591.
  • Cole CN, Hammell CM. Nucleocytoplasmic transport: driving and directing transport. Curr Biol. 1998;8(11):R368–372.
  • Kendirgi F, Barry DM, Griffis ER, et al. An essential role for hGle1 nucleocytoplasmic shuttling in mRNA export. J Cell Biol. 2003;160(7):1029–1040.
  • Kendirgi F, Rexer DJ, Alcázar-Román AR, et al. Interaction between the shuttling mRNA export factor Gle1 and the nucleoporin hCG1: a conserved mechanism in the export of Hsp70 mRNA. Mol Biol Cell. 2005;16(9):4304–4315.
  • Kaneb HM, Folkmann AW, Belzil VV, et al. Deleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis. Hum Mol Genet. 2015;24(5):1363–1373. .
  • Nousiainen HO, Kestila M, Pakkasjarvi N, et al. Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease. Nat Genet. 2008;40(2):155–157.
  • Herva R, Conradi NG, Kalimo H, et al. A syndrome of multiple congenital contractures: neuropathological analysis on five fetal cases. Am J Med Genet. 1988;29(1):67–76.
  • Vuopala K, Ignatius J, Herva R. Lethal arthrogryposis with anterior horn cell disease. Hum Pathol. 1995;26(1):12–19.
  • Cho KI, Yoon D, Qiu S, et al. Loss of Ranbp2 in motoneurons causes disruption of nucleocytoplasmic and chemokine signaling, proteostasis of hnRNPH3 and Mmp28, and development of amyotrophic lateral sclerosis-like syndromes. Dis Model Mech. 2017;10(5):559–579.
  • Hansen M, Rubinsztein DC, Walker DW. Autophagy as a promoter of longevity: insights from model organisms. Nat Rev Mol Cell Biol. 2018;19(9):579–593.
  • Cirulli ET, Lasseigne BN, Petrovski S, et al. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science. 2015;347(6229):1436–1441.
  • Fecto F, Yan J, Vemula SP, et al. SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch Neurol. 2011;68(11):1440–1446.
  • Freischmidt A, Wieland T, Richter B, et al. Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat Neurosci. 2015;18(5):631–636. .
  • Maruyama H, Morino H, Ito H, et al. Mutations of optineurin in amyotrophic lateral sclerosis. Nature. 2010;465(7295):223–226.
  • Bansal M, Moharir SC, Swarup G. Autophagy receptor optineurin promotes autophagosome formation by potentiating LC3-II production and phagophore maturation. Commun Integr Biol. 2018;11(2):1–4.
  • Oakes JA, Davies MC, Collins MO. TBK1: a new player in ALS linking autophagy and neuroinflammation. Mol Brain. 2017;10(1):5.
  • Richter B, Sliter DA, Herhaus L, et al. Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria. Proc Natl Acad Sci U S A. 2016;113(15):4039–4044.
  • Deng Z, Lim J, Wang Q, et al. ALS-FTLD-linked mutations of SQSTM1/p62 disrupt selective autophagy and NFE2L2/NRF2 anti-oxidative stress pathway. Autophagy. 2019;16(5):917–931.
  • Wong YC, Holzbaur ELF . Optineurin is an autophagy receptor for damaged mitochondria in parkin-mediated mitophagy that is disrupted by an ALS-linked mutation. Proc Natl Acad Sci U S A. 2014;111(42): E4439–E4448.
  • De Majo M, Topp SD, Smith BN, et al. ALS-associated missense and nonsense TBK1 mutations can both cause loss of kinase function. Neurobiol Aging. 2018;71:266 e261–266 e210.
  • Barmada SJ, Serio A, Arjun A, et al. Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models. Nat Chem Biol. 2014;10(8):677–685.
  • Xia Q, Wang H, Hao Z, et al. TDP-43 loss of function increases TFEB activity and blocks autophagosome-lysosome fusion. Embo J. 2016;35(2):121–142. .
  • Ling SC, Dastidar SG, Tokunaga S, et al. Overriding FUS autoregulation in mice triggers gain-of-toxic dysfunctions in RNA metabolism and autophagy-lysosome axis. Elife. 2019;8. DOI:10.7554/eLife.40811.
  • Chitiprolu M, Jagow C, Tremblay V, et al. A complex of C9ORF72 and p62 uses arginine methylation to eliminate stress granules by autophagy. Nat Commun. 2018;9(1):2794. .
  • Sullivan PM, Zhou X, Robins AM, et al. The ALS/FTLD associated protein C9orf72 associates with SMCR8 and WDR41 to regulate the autophagy-lysosome pathway. Acta Neuropathol Commun. 2016a;4(1):51.
  • Ash PE, Bieniek KF, Gendron TF, et al. Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron. 2013;77(4):639–646.
  • Boivin M, Pfister V, Gaucherot A, et al. Reduced autophagy upon C9ORF72 loss synergizes with dipeptide repeat protein toxicity in G4C2 repeat expansion disorders. Embo J. 2020;39(4). DOI:10.15252/embj.2018100574
  • Sellier C, Campanari ML, Julie Corbier C, et al. Loss of C9ORF72 impairs autophagy and synergizes with polyQ Ataxin-2 to induce motor neuron dysfunction and cell death. Embo J. 2016;35(12):1276–1297.
  • Yang M, Liang C, Swaminathan K, et al. A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy. Sci Adv. 2016;2(9):e1601167.
  • Sea K, Sohn SH, Durazo A, et al. Insights into the role of the unusual disulfide bond in copper-zinc superoxide dismutase. J Biol Chem. 2015;290(4):2405–2418
  • Xie Y, Zhou B, Lin MY, et al. Endolysosomal deficits augment mitochondria pathology in spinal motor neurons of asymptomatic fALS mice. Neuron. 2015;87(2):355–370.
  • Richard P, Feng S, Tsai YL, et al. SETX (senataxin), the helicase mutated in AOA2 and ALS4, functions in autophagy regulation. Autophagy. 2020:1–18. 10.1080/15548627.2020.1796292
  • Richard P, Feng S, Manley JL. A SUMO-dependent interaction between Senataxin and the exosome, disrupted in the neurodegenerative disease AOA2, targets the exosome to sites of transcription-induced DNA damage. Genes Dev. 2013;27(20):2227–2232.
  • Skourti-Stathaki K, Proudfoot NJ, Gromak N. Human senataxin resolves RNA/DNA hybrids formed at transcriptional pause sites to promote Xrn2-dependent termination. Mol Cell. 2011;42(6):794–805.
  • Brambati A, Colosio A, Zardoni L, et al. Replication and transcription on a collision course: eukaryotic regulation mechanisms and implications for DNA stability. Front Genet. 2015;6:166.
  • Madabhushi R, Pan L, Tsai LH. DNA damage and its links to neurodegeneration. Neuron. 2014;83(2):266–282.
  • Konopka A, Atkin JD. The emerging role of DNA damage in the pathogenesis of the C9orf72 repeat expansion in amyotrophic lateral sclerosis. Int J Mol Sci. 2018;19(10):3137.
  • Farg MA, Konopka A, Soo KY, et al. The DNA damage response (DDR) is induced by the C9orf72 repeat expansion in amyotrophic lateral sclerosis. Hum Mol Genet. 2017;26(15):2882–2896.
  • Qiu H, Lee S, Shang Y, et al. ALS-associated mutation FUS-R521C causes DNA damage and RNA splicing defects. J Clin Invest. 2014;124(3):981–999.
  • Nihei Y, Mori K, Werner G, et al. Poly-glycine-alanine exacerbates C9orf72 repeat expansion-mediated DNA damage via sequestration of phosphorylated ATM and loss of nuclear hnRNPA3. Acta Neuropathol. 2020;139(1):99–118. .
  • Wang H, Hegde ML. New mechanisms of DNA repair defects in fused in sarcoma-associated neurodegeneration: stage set for DNA repair-based therapeutics? J Exp Neurosci. 2019;13:1179069519856358.
  • Rulten SL, Rotheray A, Green RL, et al. PARP-1 dependent recruitment of the amyotrophic lateral sclerosis-associated protein FUS/TLS to sites of oxidative DNA damage. Nucleic Acids Res. 2014;42(1):307–314.
  • Naumann M, Pal A, Goswami A, et al. Impaired DNA damage response signaling by FUS-NLS mutations leads to neurodegeneration and FUS aggregate formation. Nat Commun. 2018;9(1):335. .
  • Singatulina AS, Hamon L, Sukhanova MV, et al. PARP-1 activation directs FUS to DNA damage sites to form PARG-reversible compartments enriched in damaged DNA. Cell Rep. 2019;27(6):1809–1821 e1805.
  • Hock EM, Maniecka Z, Hruska-Plochan M, et al. Hypertonic stress causes cytoplasmic translocation of neuronal, but not astrocytic, FUS due to impaired transportin function. Cell Rep. 2018;24(4):987–1000 e1007.
  • Mitra J, Guerrero EN, Hegde PM, et al. Motor neuron disease-associated loss of nuclear TDP-43 is linked to DNA double-strand break repair defects. Proc Natl Acad Sci U S A. 2019;116(10):4696–4705.
  • Freibaum BD, Taylor JP. The role of dipeptide repeats in C9ORF72-related ALS-FTD. Front Mol Neurosci. 2017;10:35.
  • Andrade NS, Ramic M, Esanov R, et al. Dipeptide repeat proteins inhibit homology-directed DNA double strand break repair in C9ORF72 ALS/FTD. Mol Neurodegener. 2020;15(1):13.
  • Lopez-Gonzalez R, Lu Y, Gendron TF, et al. Poly(GR) in C9ORF72-related ALS/FTD compromises mitochondrial function and increases oxidative stress and DNA damage in iPSC-derived motor neurons. Neuron. 2016;92(2):383–391.
  • Freibaum BD, Lu Y, Lopez-Gonzalez R, et al. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature. 2015;525(7567):129–133.
  • Takei K, Watanabe K, Yuki S, et al. Edaravone and its clinical development for a amyotrophic lateral sclerosis. Amyotroph Lat Scl Fr. 2017;18:5–10.
  • Mandrioli J, D’Amico R, Zucchi E, et al. Rapamycin treatment for amyotrophic lateral sclerosis protocol for a phase II randomized, double-blind, placebo-controlled, multicenter, clinical trial (RAP-ALS trial). Medicine (Baltimore). 2018;97(24):e11119.
  • Ly CV, Miller TM. Emerging antisense oligonucleotide and viral therapies for amyotrophic lateral sclerosis. Curr Opin Neurol. 2018;31(5):648–654.
  • Wheeler RJ, Lee HO, Poser I, et al. Small molecules for modulating protein driven liquid-liquid phase separa- 1345 tion in treating neurodegenerative disease. bioRxiv. 2019;721001. DOI:10.1101/721001.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.