FUS Interacts with HSP60 to Promote Mitochondrial Damage

English version České info

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two groups of common and devastating neurodegenerative diseases, characterized by losses of selected groups of neurons. Mutations in the FUS gene have been associated with ALS, whereas inclusion bodies containing the FUS protein have been discovered in both ALS and FTLD patients. However, the underlying pathogenic mechanisms of FUS in these diseases remain unclear. Here, we demonstrate that wild-type or ALS-associated mutant FUS can interact with mitochondrial chaperonin HSP60 and that HSP60 mediates FUS localization to mitochondria, leading to mitochondrial damage. Mitochondrial impairment may be an early event in FUS proteinopathies and represent a potential therapeutic target for treating these fatal diseases.

Vyšlo v časopise: FUS Interacts with HSP60 to Promote Mitochondrial Damage. PLoS Genet 11(9): e32767. doi:10.1371/journal.pgen.1005357
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005357

Souhrn

Zdroje

1. Aoki M, Ogasawara M, Matsubara Y, Narisawa K, Nakamura S, et al. (1993) Mild ALS in Japan associated with novel SOD mutation. Nat Genet 5: 323–324. 8298637

2. Rosen DR (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 364: 362. 8332197

3. Andersen PM, Al-Chalabi A (2011) Clinical genetics of amyotrophic lateral sclerosis: what do we really know? Nat Rev Neurol 7: 603–615. doi: 10.1038/nrneurol.2011.150 21989245

4. Da Cruz S, Cleveland DW (2011) Understanding the role of TDP-43 and FUS/TLS in ALS and beyond. Curr Opin Neurobiol 21: 904–919. doi: 10.1016/j.conb.2011.05.029 21813273

5. Morris HR, Waite AJ, Williams NM, Neal JW, Blake DJ (2012) Recent advances in the genetics of the ALS-FTLD complex. Curr Neurol Neurosci Rep 12: 243–250. doi: 10.1007/s11910-012-0268-5 22477152

6. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, et al. (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314: 130–133. 17023659

7. Kwiatkowski TJ Jr., Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, 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 19251627

8. Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL, 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 19251628

9. Hanson KA, Kim SH, Tibbetts RS (2012) RNA-binding proteins in neurodegenerative disease: TDP-43 and beyond. Wiley Interdiscip Rev RNA 3: 265–285. doi: 10.1002/wrna.111 22028183

10. Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar HA, et al. (2009) A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 132: 2922–2931. doi: 10.1093/brain/awp214 19674978

11. Neumann M, Roeber S, Kretzschmar HA, Rademakers R, Baker M, et al. (2009) Abundant FUS-immunoreactive pathology in neuronal intermediate filament inclusion disease. Acta Neuropathol 118: 605–616. doi: 10.1007/s00401-009-0581-5 19669651

12. Munoz DG, Neumann M, Kusaka H, Yokota O, Ishihara K, et al. (2009) FUS pathology in basophilic inclusion body disease. Acta Neuropathol 118: 617–627. doi: 10.1007/s00401-009-0598-9 19830439

13. Mackenzie IR, Rademakers R, Neumann M (2010) TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol 9: 995–1007. doi: 10.1016/S1474-4422(10)70195-2 20864052

14. Baloh RH (2012) How do the RNA-binding proteins TDP-43 and FUS relate to amyotrophic lateral sclerosis and frontotemporal degeneration, and to each other? Curr Opin Neurol 25: 701–707. doi: 10.1097/WCO.0b013e32835a269b 23041957

15. Mackenzie IR, Munoz DG, Kusaka H, Yokota O, Ishihara K, et al. (2011) Distinct pathological subtypes of FTLD-FUS. Acta Neuropathol 121: 207–218. doi: 10.1007/s00401-010-0764-0 21052700

16. Sabatelli M, Moncada A, Conte A, Lattante S, Marangi G, et al. (2013) Mutations in the 3' untranslated region of FUS causing FUS overexpression are associated with amyotrophic lateral sclerosis. Hum Mol Genet 22: 4748–4755. doi: 10.1093/hmg/ddt328 23847048

17. Chen Y, Yang M, Deng J, Chen X, Ye Y, et al. (2011) Expression of human FUS protein in Drosophila leads to progressive neurodegeneration. Protein Cell 2: 477–486. doi: 10.1007/s13238-011-1065-7 21748598

18. Fushimi K, Long C, Jayaram N, Chen X, Li L, et al. (2011) Expression of human FUS/TLS in yeast leads to protein aggregation and cytotoxicity, recapitulating key features of FUS proteinopathy. Protein Cell 2: 141–149. doi: 10.1007/s13238-011-1014-5 21327870

19. Huang C, Zhou H, Tong J, Chen H, Liu YJ, et al. (2011) FUS transgenic rats develop the phenotypes of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. PLoS Genet 7: e1002011. doi: 10.1371/journal.pgen.1002011 21408206

20. Ju S, Tardiff DF, Han H, Divya K, Zhong Q, et al. (2011) A yeast model of FUS/TLS-dependent cytotoxicity. PLoS Biol 9: e1001052. doi: 10.1371/journal.pbio.1001052 21541368

21. Kryndushkin D, Wickner RB, Shewmaker F (2011) FUS/TLS forms cytoplasmic aggregates, inhibits cell growth and interacts with TDP-43 in a yeast model of amyotrophic lateral sclerosis. Protein Cell 2: 223–236. doi: 10.1007/s13238-011-1525-0 21452073

22. Lanson NA Jr., Maltare A, King H, Smith R, Kim JH, et al. (2011) A Drosophila model of FUS-related neurodegeneration reveals genetic interaction between FUS and TDP-43. Hum Mol Genet 20: 2510–2523. doi: 10.1093/hmg/ddr150 21487023

23. Murakami T, Yang SP, Xie L, Kawano T, Fu D, et al. (2012) ALS mutations in FUS cause neuronal dysfunction and death in Caenorhabditis elegans by a dominant gain-of-function mechanism. Hum Mol Genet 21: 1–9. doi: 10.1093/hmg/ddr417 21949354

24. Sun Z, Diaz Z, Fang X, Hart MP, Chesi A, et al. (2011) Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS. PLoS Biol 9: e1000614. doi: 10.1371/journal.pbio.1000614 21541367

25. Verbeeck C, Deng Q, Dejesus-Hernandez M, Taylor G, Ceballos-Diaz C, et al. (2012) Expression of Fused in sarcoma mutations in mice recapitulates the neuropathology of FUS proteinopathies and provides insight into disease pathogenesis. Mol Neurodegener 7: 53. doi: 10.1186/1750-1326-7-53 23046583

26. Mitchell JC, McGoldrick P, Vance C, Hortobagyi T, Sreedharan J, 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 22961620

27. Neumann M, Valori CF, Ansorge O, Kretzschmar HA, Munoz DG, et al. (2012) Transportin 1 accumulates specifically with FET proteins but no other transportin cargos in FTLD-FUS and is absent in FUS inclusions in ALS with FUS mutations. Acta Neuropathol 124: 705–716. doi: 10.1007/s00401-012-1020-6 22842875

28. Ellis RJ (2005) Chaperomics: in vivo GroEL function defined. Curr Biol 15: R661–663. 16139196

29. Hartl FU, Martin J, Neupert W (1992) Protein folding in the cell: the role of molecular chaperones Hsp70 and Hsp60. Annu Rev Biophys Biomol Struct 21: 293–322. 1525471

30. Mayer MP (2010) Gymnastics of molecular chaperones. Mol Cell 39: 321–331. doi: 10.1016/j.molcel.2010.07.012 20705236

31. Gupta RS, Ramachandra NB, Bowes T, Singh B (2008) Unusual cellular disposition of the mitochondrial molecular chaperones Hsp60, Hsp70 and Hsp10. Novartis Found Symp 291: 59–68; discussion 69–73, 137–140. 18575266

32. Nakamura H, Minegishi H (2013) HSP60 as a drug target. Curr Pharm Des 19: 441–451. 22920899

33. Haynes CM, Ron D (2010) The mitochondrial UPR—protecting organelle protein homeostasis. J Cell Sci 123: 3849–3855. doi: 10.1242/jcs.075119 21048161

34. Heyrovska N, Frydman J, Hohfeld J, Hartl FU (1998) Directionality of polypeptide transfer in the mitochondrial pathway of chaperone-mediated protein folding. Biol Chem 379: 301–309. 9563826

35. Martin J (1997) Molecular chaperones and mitochondrial protein folding. J Bioenerg Biomembr 29: 35–43. 9067800

36. Ostermann J, Horwich AL, Neupert W, Hartl FU (1989) Protein folding in mitochondria requires complex formation with hsp60 and ATP hydrolysis. Nature 341: 125–130. 2528694

37. Hansen J, Svenstrup K, Ang D, Nielsen MN, Christensen JH, et al. (2007) A novel mutation in the HSPD1 gene in a patient with hereditary spastic paraplegia. J Neurol 254: 897–900. 17420924

38. Hansen JJ, Durr A, Cournu-Rebeix I, Georgopoulos C, Ang D, et al. (2002) Hereditary spastic paraplegia SPG13 is associated with a mutation in the gene encoding the mitochondrial chaperonin Hsp60. Am J Hum Genet 70: 1328–1332. 11898127

39. Menzies FM, Cookson MR, Taylor RW, Turnbull DM, Chrzanowska-Lightowlers ZM, et al. (2002) Mitochondrial dysfunction in a cell culture model of familial amyotrophic lateral sclerosis. Brain 125: 1522–1533. 12077002

40. Raimondi A, Mangolini A, Rizzardini M, Tartari S, Massari S, et al. (2006) Cell culture models to investigate the selective vulnerability of motoneuronal mitochondria to familial ALS-linked G93ASOD1. Eur J Neurosci 24: 387–399. 16903849

41. Vande Velde C, Miller TM, Cashman NR, Cleveland DW (2008) Selective association of misfolded ALS-linked mutant SOD1 with the cytoplasmic face of mitochondria. Proc Natl Acad Sci U S A 105: 4022–4027. doi: 10.1073/pnas.0712209105 18296640

42. Vande Velde C, McDonald KK, Boukhedimi Y, McAlonis-Downes M, Lobsiger CS, et al. (2011) Misfolded SOD1 associated with motor neuron mitochondria alters mitochondrial shape and distribution prior to clinical onset. PLoS ONE 6: e22031. doi: 10.1371/journal.pone.0022031 21779368

43. Cozzolino M, Ferri A, Valle C, Carri MT (2013) Mitochondria and ALS: implications from novel genes and pathways. Mol Cell Neurosci 55: 44–49. doi: 10.1016/j.mcn.2012.06.001 22705710

44. Shan X, Chiang PM, Price DL, Wong PC (2010) Altered distributions of Gemini of coiled bodies and mitochondria in motor neurons of TDP-43 transgenic mice. Proc Natl Acad Sci U S A 107: 16325–16330. doi: 10.1073/pnas.1003459107 20736350

45. Xu YF, Gendron TF, Zhang YJ, Lin WL, D'Alton S, 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: 10851–10859. doi: 10.1523/JNEUROSCI.1630-10.2010 20702714

46. Huang EJ, Zhang J, Geser F, Trojanowski JQ, Strober JB, et al. (2010) Extensive FUS-immunoreactive pathology in juvenile amyotrophic lateral sclerosis with basophilic inclusions. Brain Pathol 20: 1069–1076. doi: 10.1111/j.1750-3639.2010.00413.x 20579074

47. Tradewell ML, Yu Z, Tibshirani M, Boulanger MC, Durham HD, et al. (2012) Arginine methylation by PRMT1 regulates nuclear-cytoplasmic localization and toxicity of FUS/TLS harbouring ALS-linked mutations. Hum Mol Genet 21: 136–149. doi: 10.1093/hmg/ddr448 21965298

48. Aoun P, Watson DG, Simpkins JW (2003) Neuroprotective effects of PPARgamma agonists against oxidative insults in HT-22 cells. Eur J Pharmacol 472: 65–71. 12860474

49. Pilling AD, Horiuchi D, Lively CM, Saxton WM (2006) Kinesin-1 and Dynein are the primary motors for fast transport of mitochondria in Drosophila motor axons. Mol Biol Cell 17: 2057–2068. 16467387

50. Yao A, Jin S, Li X, Liu Z, Ma X, et al. (2011) Drosophila FMRP regulates microtubule network formation and axonal transport of mitochondria. Hum Mol Genet 20: 51–63. doi: 10.1093/hmg/ddq431 20935173

51. Mitra K, Rikhy R, Lilly M, Lippincott-Schwartz J (2012) DRP1-dependent mitochondrial fission initiates follicle cell differentiation during Drosophila oogenesis. J Cell Biol 197: 487–497. doi: 10.1083/jcb.201110058 22584906

52. Waterham HR, Koster J, van Roermund CW, Mooyer PA, Wanders RJ, et al. (2007) A lethal defect of mitochondrial and peroxisomal fission. N Engl J Med 356: 1736–1741. 17460227

53. Frezza C, Cipolat S, Scorrano L (2007) Organelle isolation: functional mitochondria from mouse liver, muscle and cultured fibroblasts. Nat Protoc 2: 287–295. 17406588

54. Dunkley PR, Jarvie PE, Robinson PJ (2008) A rapid Percoll gradient procedure for preparation of synaptosomes. Nat Protoc 3: 1718–1728. doi: 10.1038/nprot.2008.171 18927557

55. Verburg J, Hollenbeck PJ (2008) Mitochondrial membrane potential in axons increases with local nerve growth factor or semaphorin signaling. J Neurosci 28: 8306–8315. doi: 10.1523/JNEUROSCI.2614-08.2008 18701693

56. Wu S, Zhou F, Zhang Z, Xing D (2011) Mitochondrial oxidative stress causes mitochondrial fragmentation via differential modulation of mitochondrial fission-fusion proteins. FEBS J 278: 941–954. doi: 10.1111/j.1742-4658.2011.08010.x 21232014

57. Lashley T, Rohrer JD, Bandopadhyay R, Fry C, Ahmed Z, et al. (2011) A comparative clinical, pathological, biochemical and genetic study of fused in sarcoma proteinopathies. Brain 134: 2548–2564. doi: 10.1093/brain/awr160 21752791

58. Page T, Gitcho MA, Mosaheb S, Carter D, Chakraverty S, et al. (2011) FUS immunogold labeling TEM analysis of the neuronal cytoplasmic inclusions of neuronal intermediate filament inclusion disease: a frontotemporal lobar degeneration with FUS proteinopathy. J Mol Neurosci 45: 409–421. doi: 10.1007/s12031-011-9549-8 21603978

59. Rabbitts TH, Forster A, Larson R, Nathan P (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. 7503811

60. Lagier-Tourenne C, Polymenidou M, Cleveland DW (2010) TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration. Hum Mol Genet 19: R46–64. doi: 10.1093/hmg/ddq137 20400460

61. Traynor BJ, Singleton AB (2009) What's the FUS! Lancet Neurol 8: 418–419. doi: 10.1016/S1474-4422(09)70088-2 19375659

62. Zinszner H, Sok J, Immanuel D, Yin Y, Ron D (1997) TLS (FUS) binds RNA in vivo and engages in nucleo-cytoplasmic shuttling. J Cell Sci 110 (Pt 15): 1741–1750. 9264461

63. Truscott KN, Brandner K, Pfanner N (2003) Mechanisms of protein import into mitochondria. Current Biology 13: R326–R337. 12699647

64. Schwartz JC, Ebmeier CC, Podell ER, Heimiller J, Taatjes DJ, et al. (2013) FUS binds the CTD of RNA polymerase II and regulates its phosphorylation at Ser2 (vol 26, pg 2690, 2012). Genes & Development 27: 699–699.

65. Claros MG, Vincens P (1996) Computational method to predict mitochondrially imported proteins and their targeting sequences. Eur J Biochem 241: 779–786. 8944766

66. Young JC, Hoogenraad NJ, Hartl FU (2003) Molecular chaperones Hsp90 and Hsp70 deliver preproteins to the mitochondrial import receptor Tom70. Cell 112: 41–50. 12526792

67. Walls KC, Coskun P, Gallegos-Perez JL, Zadourian N, Freude K, et al. (2012) Swedish Alzheimer mutation induces mitochondrial dysfunction mediated by HSP60 mislocalization of amyloid precursor protein (APP) and beta-amyloid. J Biol Chem 287: 30317–30327. doi: 10.1074/jbc.M112.365890 22753410

68. Magnoni R, Palmfeldt J, Hansen J, Christensen JH, Corydon TJ, et al. (2014) The Hsp60 folding machinery is crucial for manganese superoxide dismutase folding and function. Free Radic Res 48: 168–179. doi: 10.3109/10715762.2013.858147 24151936

69. Chandra D, Choy G, Tang DG (2007) Cytosolic accumulation of HSP60 during apoptosis with or without apparent mitochondrial release—Evidence that its pro-apoptotic or pro-survival functions involve differential interactions with caspase. Journal of Biological Chemistry 282: 31289–31301. 17823127

70. Yang TT, Hsu CT, Kuo YM (2009) Amyloid precursor protein, heat-shock proteins, and Bcl-2 form a complex in mitochondria and modulate mitochondria function and apoptosis in N2a cells. Mech Ageing Dev 130: 592–601. doi: 10.1016/j.mad.2009.07.002 19622370

71. Xanthoudakis S, Roy S, Rasper D, Hennessey T, Aubin Y, et al. (1999) Hsp60 accelerates the maturation of pro-caspase-3 by upstream activator proteases during apoptosis. EMBO J 18: 2049–2056. 10205159

72. Lehnardt S, Schott E, Trimbuch T, Laubisch D, Krueger C, et al. (2008) A vicious cycle involving release of heat shock protein 60 from injured cells and activation of toll-like receptor 4 mediates neurodegeneration in the CNS. J Neurosci 28: 2320–2331. doi: 10.1523/JNEUROSCI.4760-07.2008 18322079

73. Adams MD, Celniker SE, Holt RA, Evans CA, Gocayne JD, et al. (2000) The genome sequence of Drosophila melanogaster. Science 287: 2185–2195. 10731132

74. Rubin GM, Yandell MD, Wortman JR, Gabor Miklos GL, Nelson CR, et al. (2000) Comparative genomics of the eukaryotes. Science 287: 2204–2215. 10731134

75. Baena-Lopez LA, Alonso J, Rodriguez J, Santaren JF (2008) The expression of heat shock protein HSP60A reveals a dynamic mitochondrial pattern in Drosophila melanogaster embryos. J Proteome Res 7: 2780–2788. doi: 10.1021/pr800006x 18549261

76. Timakov B, Zhang P (2001) The hsp60B gene of Drosophila melanogaster is essential for the spermatid individualization process. Cell Stress Chaperones 6: 71–77. 11525246

77. Sarkar S, Lakhotia SC (2005) The Hsp60C gene in the 25F cytogenetic region in Drosophila melanogaster is essential for tracheal development and fertility. J Genet 84: 265–281. 16385159

78. Arya R, Lakhotia SC (2008) Hsp60D is essential for caspase-mediated induced apoptosis in Drosophila melanogaster. Cell Stress Chaperones 13: 509–526. doi: 10.1007/s12192-008-0051-3 18506601

79. Ince PG, Highley JR, Kirby J, Wharton SB, Takahashi H, et al. (2011) Molecular pathology and genetic advances in amyotrophic lateral sclerosis: an emerging molecular pathway and the significance of glial pathology. Acta Neuropathol 122: 657–671. doi: 10.1007/s00401-011-0913-0 22105541

80. Lattante S, Rouleau GA, Kabashi E (2013) TARDBP and FUS mutations associated with amyotrophic lateral sclerosis: summary and update. Hum Mutat 34: 812–826. doi: 10.1002/humu.22319 23559573

81. DiMauro S, Schon EA (2008) Mitochondrial disorders in the nervous system. Annu Rev Neurosci 31: 91–123. doi: 10.1146/annurev.neuro.30.051606.094302 18333761

82. Lezi E, Swerdlow RH (2012) Mitochondria in neurodegeneration. Adv Exp Med Biol 942: 269–286. doi: 10.1007/978-94-007-2869-1_12 22399427

83. Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443: 787–795. 17051205

84. Spinazzi M, Cazzola S, Bortolozzi M, Baracca A, Loro E, et al. (2008) A novel deletion in the GTPase domain of OPA1 causes defects in mitochondrial morphology and distribution, but not in function. Hum Mol Genet 17: 3291–3302. doi: 10.1093/hmg/ddn225 18678599

85. Dormann D, Rodde R, Edbauer D, Bentmann E, Fischer I, 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 20606625

86. Baumer D, Hilton D, Paine SM, Turner MR, Lowe J, et al. (2010) Juvenile ALS with basophilic inclusions is a FUS proteinopathy with FUS mutations. Neurology 75: 611–618. doi: 10.1212/WNL.0b013e3181ed9cde 20668261

87. Chio A, Restagno G, Brunetti M, Ossola I, Calvo A, et al. (2009) Two Italian kindreds with familial amyotrophic lateral sclerosis due to FUS mutation. Neurobiol Aging 30: 1272–1275. doi: 10.1016/j.neurobiolaging.2009.05.001 19450904

88. Kabashi E, Bercier V, Lissouba A, Liao M, Brustein E, 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 21829392

89. Wang JW, Brent JR, Tomlinson A, Shneider NA, McCabe BD (2011) The ALS-associated proteins FUS and TDP-43 function together to affect Drosophila locomotion and life span. J Clin Invest 121: 4118–4126. doi: 10.1172/JCI57883 21881207

90. Li Y, Ray P, Rao EJ, Shi C, Guo W, et al. (2010) A Drosophila model for TDP-43 proteinopathy. Proc Natl Acad Sci U S A 107: 3169–3174. doi: 10.1073/pnas.0913602107 20133767

91. Li HS, Chen JH, Wu W, Fagaly T, Zhou L, et al. (1999) Vertebrate slit, a secreted ligand for the transmembrane protein roundabout, is a repellent for olfactory bulb axons. Cell 96: 807–818. 10102269

92. Wu W, Wong K, Chen J, Jiang Z, Dupuis S, et al. (1999) Directional guidance of neuronal migration in the olfactory system by the protein Slit. Nature 400: 331–336. 10432110

93. Yuasa-Kawada J, Kinoshita-Kawada M, Wu G, Rao Y, Wu JY (2009) Midline crossing and Slit responsiveness of commissural axons require USP33. Nat Neurosci 12: 1087–1089. doi: 10.1038/nn.2382 19684588

94. Guo W, Chen Y, Zhou X, Kar A, Ray P, et al. (2011) An ALS-associated mutation affecting TDP-43 enhances protein aggregation, fibril formation and neurotoxicity. Nat Struct Mol Biol 18: 822–830. doi: 10.1038/nsmb.2053 21666678

95. Orozco D, Tahirovic S, Rentzsch K, Schwenk BM, Haass C, et al. (2012) Loss of fused in sarcoma (FUS) promotes pathological Tau splicing. EMBO Rep 13: 759–764. doi: 10.1038/embor.2012.90 22710833

96. Yano H, Baranov SV, Baranova OV, Kim J, Pan Y, et al. (2014) Inhibition of mitochondrial protein import by mutant huntingtin. Nat Neurosci 17: 822–831. doi: 10.1038/nn.3721 24836077

97. Liu-Yesucevitz L, Bilgutay A, Zhang YJ, Vanderweyde T, Citro A, 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: e13250. doi: 10.1371/journal.pone.0013250 20948999

98. Song W, Chen J, Petrilli A, Liot G, Klinglmayr E, et al. (2011) Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity. Nat Med 17: 377–382. doi: 10.1038/nm.2313 21336284

99. Paumard P, Vaillier J, Coulary B, Schaeffer J, Soubannier V, et al. (2002) The ATP synthase is involved in generating mitochondrial cristae morphology. EMBO J 21: 221–230. 11823415

100. Gavin PD, Prescott M, Luff SE, Devenish RJ (2004) Cross-linking ATP synthase complexes in vivo eliminates mitochondrial cristae. J Cell Sci 117: 2333–2343. 15126633