Biology and pathobiology of TDP-43 and emergent therapeutic strategies

Cold Spring Harbor Perspectives in Medicine

Volumn 7, Issue 9, 2017, Pages

  Guo, Lin ^a   Shorter, James ^a  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ATAXIN 2; DBR1 PROTEIN; INITIATION FACTOR 2ALPHA; PROTEIN; RIBONUCLEOPROTEIN; TAR DNA BINDING PROTEIN; UNCLASSIFIED DRUG; DNA BINDING PROTEIN; RNA BINDING PROTEIN; TDP-43 PROTEIN, HUMAN;

AMYOTROPHIC LATERAL SCLEROSIS; ARTICLE; DEGENERATIVE DISEASE; GENE MUTATION; HUMAN; NONHUMAN; NUCLEOCYTOPLASMIC TRANSPORT; PATHOGENESIS; PATHOLOGY; PHASE TRANSITION; PROTEIN ASSEMBLY; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN MISFOLDING; PROTEIN PHOSPHORYLATION; PROTEIN STABILITY; PROTEIN STRUCTURE; RISK FACTOR; TDP 43 PROTEINOPATHY; GENETICS; MUTATION;

DNA-BINDING PROTEINS; HUMANS; MUTATION; RNA-BINDING PROTEINS; TDP-43 PROTEINOPATHIES;

EID: 85028951072     PISSN: None     EISSN: 21571422     Source Type: Journal    
DOI: 10.1101/cshperspect.a024554     Document Type: Article

References (286)

1. Acharya KK, Govind CK, Shore AN, Stoler MH, Reddi PP. 2006. cis-Requirement for the maintenance of round spermatid-specific transcription. Dev Biol 295: 781-790.
2. Alami NH, Smith RB, Carrasco MA, Williams LA, Winborn CS, Han SS, Kiskinis E, Winborn B, Freibaum BD, Kanagaraj A, et al. 2014. Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations. Neuron 81: 536-543.
3. Alberti S, Halfmann R, King O, Kapila A, Lindquist S. 2009. A systematic survey identifies prions and illuminates sequence features of prionogenic proteins. Cell 137: 146-158.
4. Amador-Ortiz C, Lin WL, Ahmed Z, Personett D, Davies P, Duara R, Graff-Radford NR, Hutton ML, Dickson DW. 2007. TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer’s disease. Ann Neurol 61: 435-445.
5. Anderson P, Kedersha N. 2008. Stress granules: The Tao of RNA triage. Trends Biochem Sci 33: 141-150.
6. Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, Mann D, Tsuchiya K, Yoshida M, Hashizume Y, et al. 2006. TDP-43 is a component of ubiquitin-positive taunegative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351: 602-611.
7. Armakola M, Higgins MJ, Figley MD, Barmada SJ, Scarborough EA, Diaz Z, Fang X, Shorter J, Krogan NJ, Finkbeiner S, et al. 2012. Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models. Nat Genet 44: 1302-1309.
8. Ash PE, Zhang YJ, Roberts CM, Saldi T, Hutter H, Buratti E, Petrucelli L, Link CD. 2010. Neurotoxic effects of TDP-43 overexpression in C. elegans. Hum Mol Genet 19: 3206-3218.
9. Avendano-Vazquez SE, Dhir A, Bembich S, Buratti E, Proudfoot N, Baralle FE. 2012. Autoregulation of TDP-43mRNA levels involves interplay between transcription, splicing, and alternative polyA site selection. Genes Dev 26: 1679-1684.
10. Axten JM, Medina JR, Feng Y, Shu A, Romeril SP, Grant SW, Li WH, Heerding DA, Minthorn E, Mencken T, et al. 2012. Discovery of 7-methyl-5-(1-f[3-(trifluoromethyl) phenyl]acetylg-2, 3-dihydro-1H-indol-5-yl)-7Hpyrrolo[2, 3-d]pyrimidin-4-amine (GSK2606414), a potent and selective first-in-class inhibitor of protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). J Med Chem 55: 7193-7207.
11. Axten JM, Romeril SP, Shu A, Ralph J, Medina JR, Feng Y, Li WH, Grant SW, Heerding DA, Minthorn E, et al. 2013. Discovery of GSK2656157: An optimized PERK inhibitor selected for preclinical development. ACSMed Chem Lett 4: 964-968.
12. Ayala YM, Pantano S, D’Ambrogio A, Buratti E, Brindisi A, Marchetti C, Romano M, Baralle FE. 2005. Human, Drosophila, and C. elegans TDP43: Nucleic acid binding properties and splicing regulatory function. J Mol Biol 348: 575-588.
13. Ayala YM, Pagani F, Baralle FE. 2006. TDP43 depletion rescues aberrant CFTR exon 9 skipping. FEBS Lett 580: 1339-1344.
14. Ayala YM, Zago P, D’Ambrogio A, Xu YF, Petrucelli L, Buratti E, Baralle FE. 2008. Structural determinants of the cellular localization and shuttling of TDP-43. J Cell Sci 121: 3778-3785.
15. Ayala YM, De Conti L, Avendano-Vazquez SE, Dhir A, Romano M, D’Ambrogio A, Tollervey J, Ule J, Baralle M, Buratti E, et al. 2011. TDP-43 regulates its mRNA levels through a negative feedback loop. EMBO J 30: 277-288.
16. Barmada SJ, Skibinski G, Korb E, Rao EJ, Wu JY, Finkbeiner S. 2010. Cytoplasmic mislocalization of TDP-43 is toxic to neurons and enhanced by a mutation associated with familial amyotrophic lateral sclerosis. J Neurosci 30: 639-649.
17. Barmada SJ, Serio A, Arjun A, Bilican B, Daub A, Ando DM, Tsvetkov A, Pleiss M, Li X, Peisach D, et al. 2014. Autophagy induction enhances TDP43 turnover and survival in neuronal ALS models. Nat Chem Biol 10: 677-685.
18. Benatar M, Wuu J, Fernandez C, Weihl CC, Katzen H, Steele J, Oskarsson B, Taylor JP. 2013. Motor neuron involvement in multisystem proteinopathy: Implications for ALS. Neurology 80: 1874-1880.
19. Bensimon G, Lacomblez L, Meininger V. 1994. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N Engl J Med 330: 585-591.
20. Bentmann E, Neumann M, Tahirovic S, Rodde R, Dormann D, Haass C. 2012. Requirements for stress granule recruitment of fused in sarcoma (FUS) and TAR DNA-binding protein of 43 kDa (TDP-43). J Biol Chem 287: 23079-23094.
21. Berchowitz LE, Kabachinski G, Walker MR, Carlile TM, Gilbert WV, Schwartz TU, Amon A. 2015. Regulated formation of an amyloid-like translational repressor governs gametogenesis. Cell 163: 406-418.
22. Bonini NM, Gitler AD. 2011. Model organisms reveal insight into human neurodegenerative disease: Ataxin-2 intermediate-length polyglutamine expansions are a risk factor for ALS. J Mol Neurosci 45: 676-683.
23. Brettschneider J, Del Tredici K, Toledo JB, Robinson JL, Irwin DJ, Grossman M, Suh E, Van Deerlin VM, Wood EM, Baek Y, et al. 2013. Stages of pTDP-43 pathology in amyotrophic lateral sclerosis. Ann Neurol 74: 20-38.
24. Brettschneider J, Arai K, Del Tredici K, Toledo JB, Robinson JL, Lee EB, Kuwabara S, Shibuya K, Irwin DJ, Fang L, et al. 2014. TDP-43 pathology and neuronal loss in amyotrophic lateral sclerosis spinal cord. Acta Neuropathol 128: 423-437.
25. Buchan JR, Kolaitis RM, Taylor JP, Parker R. 2013. Eukaryotic stress granules are cleared by autophagy and Cdc48/ VCP function. Cell 153: 1461-1474.
26. Budini M, Romano V, Quadri Z, Buratti E, Baralle FE. 2015. TDP-43 loss of cellular function through aggregation requires additional structural determinants beyond its C-terminal Q/N prion-like domain. Hum Mol Genet 24: 9-20.
27. Bulawa CE, Connelly S, Devit M, Wang L, Weigel C, Fleming JA, Packman J, Powers ET, Wiseman RL, Foss TR, et al. 2012. Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade. Proc Natl Acad Sci 109: 9629-9634.
28. Buratti E, Baralle FE. 2001. Characterization and functional implications of the RNA binding properties of nuclear factor TDP-43, a novel splicing regulator of CFTRexon 9. J Biol Chem 276: 36337-36343.
29. Buratti E, Brindisi A, Pagani F, Baralle FE. 2004. Nuclear factor TDP-43 binds to the polymorphic TG repeats in CFTR intron 8 and causes skipping of exon 9: A functional link with disease penetrance. Am J Hum Genet 74: 1322-1325.
30. Buratti E, Brindisi A, Giombi M, Tisminetzky S, Ayala YM, Baralle FE. 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: 37572-37584.
31. Caccamo A, Majumder S, Oddo S. 2012. Cognitive decline typical of frontotemporal lobar degeneration in transgenic mice expressing the 25-kDa C-terminal fragment of TDP-43. Am J Pathol 180: 293-302.
32. Chapman KB, Boeke JD. 1991. Isolation and characterization of the gene encoding yeast debranching enzyme. Cell 65: 483-492.
33. Chen AK, Lin RY, Hsieh EZ, Tu PH, Chen RP, Liao TY, Chen W, Wang CH, Huang JJ. 2010. Induction of amyloid fibrils by the C-terminal fragments of TDP-43 in amyotrophic lateral sclerosis. J Am Chem Soc 132: 1186-1187.
34. Chen-Plotkin AS, Lee VM, Trojanowski JQ. 2010. TAR DNA-binding protein 43 in neurodegenerative disease. Nat Rev Neurol 6: 211-220.
35. Cherkasov V, Hofmann S, Druffel-Augustin S, Mogk A, Tyedmers J, Stoecklin G, Bukau B. 2013. Coordination of translational control and protein homeostasis during severe heat stress. Curr Biol 23: 2452-2462.
36. Chiang PM, Ling J, Jeong YH, Price DL, Aja SM, Wong PC. 2010. Deletion of TDP-43 down-regulates Tbc1d1, a gene linked to obesity, and alters body fat metabolism. Proc Natl Acad Sci 107: 16320-16324.
37. Clavel F, Hance AJ. 2004. HIV drug resistance. N Engl JMed 350: 1023-1035.
38. Cohen TJ, Hwang AW, Restrepo CR, Yuan CX, Trojanowski JQ, Lee VM. 2015. An acetylation switch controls TDP-43 function and aggregation propensity. Nat Commun 6: 5845.
39. Colby DW, Giles K, Legname G, Wille H, Baskakov IV, DeArmond SJ, Prusiner SB. 2009. Design and construction of diverse mammalian prion strains. Proc Natl Acad Sci 106: 20417-20422.
40. Conicella AE, Zerze GH, Mittal J, Fawzi NL. 2016. ALS mutations disrupt phase separation mediated by a-helical structure in the TDP-43 low-complexity C-terminal domain. Structure 24: 1537-1549.
41. Couthouis J, Hart MP, Shorter J, DeJesus-Hernandez M, Erion R, Oristano R, Liu AX, Ramos D, Jethava N, Hosangadi D, et al. 2011. A yeast functional screen predicts new candidate ALS disease genes. Proc Natl Acad Sci 108: 20881-20890.
42. Couthouis J, Hart MP, Erion R, King OD, Diaz Z, Nakaya T, Ibrahim F, Kim HJ, Mojsilovic-Petrovic J, Panossian S, et al. 2012. Evaluating the role of the FUS/TLS-related gene EWSR1 in amyotrophic lateral sclerosis. Hum Mol Genet 21: 2899-2911.
43. Couthouis J, Raphael AR, Daneshjou R, Gitler AD. 2014. Targeted exon capture and sequencing in sporadic amyotrophic lateral sclerosis. PLoS Genet 10: e1004704.
44. Coyne AN, Siddegowda BB, Estes PS, Johannesmeyer J, Kovalik T, Daniel SG, Pearson A, Bowser R, Zarnescu DC. 2014. Futsch/MAP1B mRNA is a translational target of TDP-43 and is neuroprotective in a Drosophila model of amyotrophic lateral sclerosis. J Neurosci 34: 15962-15974.
45. Cushman M, Johnson BS, King OD, Gitler AD, Shorter J. 2010. Prion-like disorders: Blurring the divide between transmissibility and infectivity. J Cell Sci 123: 1191-1201.
46. 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.
47. D’Ambrogio A, Buratti E, Stuani C, Guarnaccia C, Romano M, Ayala YM, Baralle FE. 2009. Functional mapping of the interaction between TDP-43 and hnRNP A2 in vivo. Nucleic Acids Res 37: 4116-4126.
48. Das I, Krzyzosiak A, Schneider K, Wrabetz L, D’Antonio M, Barry N, Sigurdardottir A, Bertolotti A. 2015. Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit. Science 348: 239-242.
49. Davidson Y, Kelley T, Mackenzie IR, Pickering-Brown S, Du Plessis D, Neary D, Snowden JS, Mann DM. 2007. Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43. Acta Neuropathol 113: 521-533.
50. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, Rutherford NJ, Nicholson AM, Finch NA, Flynn H, Adamson J, et al. 2011. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72: 245-256.
51. Deleault NR, Lucassen RW, Supattapone S. 2003. RNA molecules stimulate prion protein conversion. Nature 425: 717-720.
52. Deng HX, Zhai H, Bigio EH, Yan J, Fecto F, Ajroud K, Mishra M, Ajroud-Driss S, Heller S, Sufit R, et al. 2010. FUSimmunoreactive inclusions are a common feature in sporadic and non-SOD1 familial amyotrophic lateral sclerosis. Ann Neurol 67: 739-748.
53. Deng HX, Chen W, Hong ST, Boycott KM, Gorrie GH, Siddique N, Yang Y, Fecto F, Shi Y, Zhai H, et al. 2011. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 477: 211-215.
54. Drisaldi B, Colnaghi L, Fioriti L, Rao N, Myers C, Snyder AM, Metzger DJ, Tarasoff J, Konstantinov E, Fraser PE, et al. 2015. SUMOylation is an inhibitory constraint that regulates the prion-like aggregation and activity of CPEB3. Cell Rep 11: 1694-1702.
55. Duennwald ML, Shorter J. 2010. Countering amyloid polymorphism and drug resistance with minimal drug cocktails. Prion 4: 244-251.
56. Duennwald ML, Echeverria A, Shorter J. 2012. Small heat shock proteins potentiate amyloid dissolution by protein disaggregases from yeast and humans. PLoS Biol 10: e1001346.
57. Eisenberg D, Jucker M. 2012. The amyloid state of proteins in human diseases. Cell 148: 1188-1203.
58. Elden AC, Kim HJ, Hart MP, Chen-Plotkin AS, Johnson BS, Fang X, Armakola M, Geser F, Greene R, Lu MM, et al. 2010. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466: 1069-1075.
59. Erives AJ, Fassler JS. 2015. Metabolic and chaperone gene loss marks the origin of animals: Evidence for Hsp104 and Hsp78 chaperones sharing mitochondrial enzymes as clients. PLoS ONE 10: e0117192.
60. Estes PS, Boehringer A, Zwick R, Tang JE, Grigsby B, Zarnescu DC. 2011. Wild-type and A315T mutant TDP-43 exert differential neurotoxicity in a Drosophila model of ALS. Hum Mol Genet 20: 2308-2321.
61. Fang YS, Tsai KJ, Chang YJ, Kao P, Woods R, Kuo PH, Wu CC, Liao JY, Chou SC, Lin V, et al. 2014. Full-length TDP-43 forms toxic amyloid oligomers that are present in frontotemporal lobar dementia-TDP patients. Nat Commun 5: 4824.
62. Feiguin F, Godena VK, Romano G, D’Ambrogio A, Klima R, Baralle FE. 2009. Depletion of TDP-43 affects Drosophila motoneurons terminal synapsis and locomotive behavior. FEBS Lett 583: 1586-1592.
63. Feiler MS, Strobel B, Freischmidt A, Helferich AM, Kappel J, Brewer BM, Li D, Thal DR, Walther P, Ludolph AC, et al. 2015. TDP-43 is intercellularly transmitted across axon terminals. J Cell Biol 211: 897-911.
64. Fiesel FC, Weber SS, Supper J, Zell A, Kahle PJ. 2012. TDP-43 regulates global translational yield by splicing of exon junction complex component SKAR. Nucleic Acids Res 40: 2668-2682.
65. Figley MD, Gitler AD. 2013. Yeast genetic screen reveals novel therapeutic strategy for ALS. Rare Dis 1: e24420.
66. Fioriti L, Myers C, Huang YY, Li X, Stephan JS, Trifilieff P, Colnaghi L, Kosmidis S, Drisaldi B, Pavlopoulos E, et al. 2015. The persistence of hippocampal-based memory requires protein synthesis mediated by the prion-like protein CPEB3. Neuron 86: 1433-1448.
67. Ford AF, Shorter J. 2015. Fleeting amyloid-like forms of Rim4 ensure meiotic fidelity. Cell 163: 275-276.
68. Fox BW, Tibbetts RS. 2015. Neurodegeneration: Problems at the nuclear pore. Nature 525: 36-37.
69. Freibaum BD, Chitta RK, High AA, Taylor JP. 2010. Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery. J Proteome Res 9: 1104-1120.
70. Freibaum BD, Lu Y, Lopez-Gonzalez R, Kim NC, Almeida S, Lee KH, Badders N, Valentine M, Miller BL, Wong PC, et al. 2015. GGGGCCrepeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature 525: 129-133.
71. Fuentealba RA, Udan M, Bell S, Wegorzewska I, Shao J, Diamond MI, Weihl CC, Baloh RH. 2010. Interaction with polyglutamine aggregates reveals a Q/N-rich domain in TDP-43. J Biol Chem 285: 26304-26314.
72. Fujita Y, Fujita S, Takatama M, Ikeda M, Okamoto K. 2011. Numerous FUS-positive inclusions in an elderly woman with motor neuron disease. Neuropathology 31: 170-176.
73. Furukawa Y, Kaneko K, Watanabe S, Yamanaka K, Nukina N. 2011. A seeding reaction recapitulates intracellular formation of Sarkosyl-insoluble transactivation response element (TAR) DNA-binding protein-43 inclusions. J Biol Chem 286: 18664-18672.
74. Gao X, Carroni M, Nussbaum-Krammer C, Mogk A, Nillegoda NB, Szlachcic A, Guilbride DL, Saibil HR, Mayer MP, Bukau B. 2015. Human Hsp70 disaggregase reverses parkinson’s-linked a-synuclein amyloid fibrils. Mol Cell 59: 781-793.
75. Geser F, Martinez-Lage M, Robinson J, Uryu K, Neumann M, Brandmeir NJ, Xie SX, Kwong LK, Elman L, McCluskey L, et al. 2009. Clinical and pathological continuum of multisystem TDP-43 proteinopathies. Arch Neurol 66: 180-189.
76. Gispert S, Kurz A, Waibel S, Bauer P, Liepelt I, Geisen C, Gitler AD, Becker T, Weber M, Berg D, et al. 2012. The modulation of amyotrophic lateral sclerosis risk by ataxin-2 intermediate polyglutamine expansions is a specific effect. Neurobiol Dis 45: 356-361.
77. Gitcho MA, Baloh RH, Chakraverty S, Mayo K, Norton JB, Levitch D, Hatanpaa KJ, White CL III, Bigio EH, Caselli R, et al. 2008. TDP-43 A315Tmutation in familial motor neuron disease. Ann Neurol 63: 535-538.
78. Gitcho MA, Bigio EH, Mishra M, Johnson N, Weintraub S, Mesulam M, Rademakers R, Chakraverty S, Cruchaga C, Morris JC, et al. 2009. TARDBP 30-UTR variant in autopsy-confirmed frontotemporal lobar degeneration with TDP-43 proteinopathy. Acta Neuropathol 118: 633-645.
79. Gitler AD, Shorter J. 2011. RNA-binding proteins with prion-like domains in ALS and FTLD-U. Prion 5: 179-187.
80. Goldschmidt L, Teng PK, Riek R, Eisenberg D. 2010. Identifying the amylome, proteins capable of forming amyloid-like fibrils. Proc Natl Acad Sci 107: 3487-3492.
81. Grabbe C, Dikic I. 2009. Functional roles of ubiquitin-like domain (ULD) and ubiquitin-binding domain (UBD) containing proteins. Chem Rev 109: 1481-1494.
82. Grad LI, Fernando SM, Cashman NR. 2015. From molecule to molecule and cell to cell: Prion-like mechanisms in amyotrophic lateral sclerosis. Neurobiol Dis 77: 257-265.
83. Gros-Louis F, Gaspar C, Rouleau GA. 2006. Genetics of familial and sporadic amyotrophic lateral sclerosis. Biochim Biophys Acta 1762: 956-972.
84. Guo L, Shorter J. 2015. It’s raining liquids: RNA tunes viscoelasticity and dynamics of membraneless organelles. Mol Cell 60: 189-192.
85. Guo W, Chen Y, Zhou X, Kar A, Ray P, Chen X, Rao EJ, Yang M, Ye H, Zhu L, et al. 2011. An ALS-associated mutation affecting TDP-43 enhances protein aggregation, fibril formation and neurotoxicity. Nat Struct Mol Biol 18: 822-830.
86. Haines JD, Herbin O, de la Hera B, Vidaurre OG, Moy GA, Sun Q, Fung HY, Albrecht S, Alexandropoulos K, McCauley D, et al. 2015. Nuclear export inhibitors avert progression in preclinical models of inflammatory demyelination. Nat Neurosci 18: 511-520.
87. Halfmann R, Jarosz DF, Jones SK, Chang A, Lancaster AK, Lindquist S. 2012. Prions are a common mechanism for phenotypic inheritance in wild yeasts. Nature 482: 363-368.
88. Halliday M, Radford H, Sekine Y, Moreno J, Verity N, le Quesne J, Ortori CA, Barrett DA, Fromont C, Fischer PM, et al. 2015. Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity. Cell Death Dis 6: e1672.
89. Hammarstrom P, Wiseman RL, Powers ET, Kelly JW. 2003. Prevention of transthyretin amyloid disease by changing protein misfolding energetics. Science 299: 713-716.
90. Han TW, Kato M, Xie S, Wu LC, Mirzaei H, Pei J, Chen M, Xie Y, Allen J, Xiao G, et al. 2012. Cell-free formation of RNA granules: Bound RNAs identify features and components of cellular assemblies. Cell 149: 768-779.
91. Hanson KA, Kim SH, Wassarman DA, Tibbetts RS. 2010. Ubiquilin modifiesTDP-43 toxicity in a Drosophila model of amyotrophic lateral sclerosis (ALS). J Biol Chem 285: 11068-11072.
92. Harding HP, Zeng H, Zhang Y, Jungries R, Chung P, Plesken H, Sabatini DD, Ron D. 2001. Diabetes mellitus and exocrine pancreatic dysfunction in perk2/2 mice reveals a role for translational control in secretory cell survival. Mol Cell 7: 1153-1163.
93. Hart MP, Gitler AD. 2012. ALS-associated ataxin 2 polyQ expansions enhance stress-induced caspase 3 activation and increase TDP-43 pathological modifications. J Neurosci 32: 9133-9142.
94. Hart MP, Brettschneider J, Lee VM, Trojanowski JQ, Gitler AD. 2012. Distinct TDP-43 pathology in ALS patients with ataxin 2 intermediate-length polyQ expansions. Acta Neuropathol 124: 221-230.
95. Hewitt C, Kirby J, Highley JR, Hartley JA, Hibberd R, Hollinger HC, Williams TL, Ince PG, McDermott CJ, Shaw PJ. 2010. Novel FUS/TLS mutations and pathology in familial and sporadic amyotrophic lateral sclerosis. Arch Neurol 67: 455-461.
96. Huang YC, Lin KF, He RY, Tu PH, Koubek J, Hsu YC, Huang JJ. 2013. Inhibition of TDP-43 aggregation by nucleic acid binding. PLoS ONE 8: e64002.
97. Hurshman AR, White JT, Powers ET, Kelly JW. 2004. Transthyretin aggregation under partially denaturing conditions is a downhill polymerization. Biochemistry 43: 7365-7381.
98. Igaz LM, Kwong LK, Lee EB, Chen-Plotkin A, Swanson E, Unger T, Malunda J, Xu Y, Winton MJ, Trojanowski JQ, et al. 2011. Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice. J Clin Invest 121: 726-738.
99. Iguchi Y, Katsuno M, Niwa J, Takagi S, Ishigaki S, Ikenaka K, Kawai K, Watanabe H, Yamanaka K, Takahashi R, et al. 2013. Loss of TDP-43 causes age-dependent progressive motor neuron degeneration. Brain 136: 1371-1382.
100. Imbert G, Saudou F, Yvert G, Devys D, Trottier Y, Garnier JM, Weber C, Mandel JL, Cancel G, Abbas N, et al. 1996. Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats. Nat Genet 14: 285-291.
101. Irwin DJ, Cairns NJ, Grossman M, McMillan CT, Lee EB, Van Deerlin VM, Lee VM, Trojanowski JQ. 2015. Frontotemporal lobar degeneration: Defining phenotypic diversity through personalized medicine. Acta Neuropathol 129: 469-491.
102. Jablonski MR, Markandaiah SS, Jacob D, Meng NJ, Li K, Gennaro V, Lepore AC, Trotti D, Pasinelli P. 2014. Inhibiting drug efflux transporters improves efficacy of ALS therapeutics. Ann Clin Transl Neurol 1: 996-1005.
103. Jackrel ME, Shorter J. 2014a. Potentiated Hsp104 variants suppress toxicity of diverse neurodegenerative diseaselinked proteins. Dis Model Mech 7: 1175-1184.
104. Jackrel ME, Shorter J. 2014b. Reversing deleterious protein aggregation with re-engineered protein disaggregases. Cell Cycle 13: 1379-1383.
105. Jackrel ME, Shorter J. 2015. Engineering enhanced protein disaggregases for neurodegenerative disease. Prion 9: 90-109.
106. Jackrel ME, DeSantis ME, Martinez BA, Castellano LM, Stewart RM, Caldwell KA, Caldwell GA, Shorter J. 2014a. Potentiated Hsp104 variants antagonize diverse proteotoxic misfolding events. Cell 156: 170-182.
107. Jackrel ME, Tariq A, Yee K, Weitzman R, Shorter J. 2014b. Isolating potentiated Hsp104 variants using yeast proteinopathy models. J Vis Exp 93: e52089.
108. Jain S, Wheeler JR, Walters RW, Agrawal A, Barsic A, Parker R. 2016. ATPase-modulated stress granules contain a diverse proteome and substructure. Cell 164: 487-498.
109. Johnson BS, McCaffery JM, Lindquist S, Gitler AD. 2008. A yeast TDP-43 proteinopathy model: Exploring the molecular determinants of TDP-43 aggregation and cellular toxicity. Proc Natl Acad Sci 105: 6439-6444.
110. Johnson BS, Snead D, Lee JJ, McCaffery JM, Shorter J, Gitler AD. 2009. TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity. J Biol Chem 284: 20329-20339.
111. Johnson JO, Mandrioli J, Benatar M, Abramzon Y, Van Deerlin VM, Trojanowski JQ, Gibbs JR, Brunetti M, Gronka S, Wuu J, et al. 2010. Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68: 857-864.
112. Josephs KA, Murray ME, Whitwell JL, Parisi JE, Petrucelli L, Jack CR, Petersen RC, Dickson DW. 2014a. Staging TDP-43 pathology in Alzheimer’s disease. Acta Neuropathol 127: 441-450.
113. Josephs KA, Whitwell JL, Weigand SD, Murray ME, Tosakulwong N, Liesinger AM, Petrucelli L, Senjem ML, Knopman DS, Boeve BF, et al. 2014b. TDP-43 is a key player in the clinical features associated with Alzheimer’s disease. Acta Neuropathol 127: 811-824.
114. Josephs KA, Murray ME, Whitwell JL, Tosakulwong N, Weigand SD, Petrucelli L, Liesinger AM, Petersen RC, Parisi JE, Dickson DW. 2016. Updated TDP-43 in Alzheimer’s disease staging scheme. Acta Neuropathol 131: 571-585.
115. Jovicic A, Gitler AD. 2014. TDP-43 in ALS: Stay on target... almost there. Neuron 81: 463-465.
116. Jovicic A, Mertens J, Boeynaems S, Bogaert E, Chai N, Yamada SB, Paul JW 3rd, Sun S, Herdy JR, Bieri G, et al. 2015. Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nat Neurosci 18: 1226-1229.
117. Jung Y, Dickson DW, Murray ME, Whitwell JL, Knopman DS, Boeve BF, Jack CR Jr, Parisi JE, Petersen RC, Josephs KA. 2014. TDP-43 in Alzheimer’s disease is not associated with clinical FTLD or Parkinsonism. J Neurol 261: 1344-1348.
118. Kabashi E, Valdmanis PN, Dion P, Spiegelman D, McConkey BJ, Vande Velde C, Bouchard JP, Lacomblez L, Pochigaeva K, Salachas F, et al. 2008. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 40: 572-574.
119. Kabashi E, Lin L, Tradewell ML, Dion PA, Bercier V, Bourgouin P, Rochefort D, Bel Hadj S, Durham HD, Vande Velde C, et al. 2010. Gain and loss of function of ALSrelated mutations of TARDBP (TDP-43) cause motor deficits in vivo. Hum Mol Genet 19: 671-683.
120. Kato M, Han TW, Xie S, Shi K, Du X, Wu LC, Mirzaei H, Goldsmith EJ, Longgood J, Pei J, et al. 2012. Cell-free formation of RNA granules: Low complexity sequence domains form dynamic fibers within hydrogels. Cell 149: 753-767.
121. Kawahara Y, Mieda-Sato A. 2012. TDP-43 promotes micro-RNA biogenesis as a component of the Drosha and Dicer complexes. Proc Natl Acad Sci 109: 3347-3352.
122. Kayed R, Head E, Thompson JL, McIntire TM, Milton SC, Cotman CW, Glabe CG. 2003. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300: 486-489.
123. Khan MR, Li L, Perez-Sanchez C, Saraf A, Florens L, Slaughter BD, Unruh JR, Si K. 2015. Amyloidogenic oligomerization transforms Drosophila Orb2 from a translation repressor to an activator. Cell 163: 1468-1483.
124. Kiehl TR, Nechiporuk A, Figueroa KP, Keating MT, Huynh DP, Pulst SM. 2006. Generation and characterization of Sca2 (ataxin-2) knockout mice. Biochem Biophys Res Commun 339: 17-24.
125. Kim SH, Shanware NP, Bowler MJ, Tibbetts RS. 2010. Amyotrophic lateral sclerosis-associated proteins TDPTDP 43 and FUS/TLS function in a common biochemical complex to co-regulate HDAC6 mRNA. J Biol Chem 285: 34097-34105.
126. Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, MacLea KS, Freibaum B, Li S, Molliex A, et al. 2013. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495: 467-473.
127. Kim HJ, Raphael AR, LaDow ES, McGurk L, Weber RA, Trojanowski JQ, Lee VM, Finkbeiner S, Gitler AD, Bonini NM. 2014. Therapeutic modulation of eIF2a phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models. Nat Genet 46: 152-160.
128. King OD, Gitler AD, Shorter J. 2012. The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease. Brain Res 1462: 61-80.
129. Kraemer BC, Schuck T, Wheeler JM, Robinson LC, Trojanowski JQ, Lee VM, Schellenberg GD. 2010. Loss of murine TDP-43 disrupts motor function and plays an essential role in embryogenesis. Acta Neuropathol 119: 409-419.
130. Kroschwald S, Maharana S, Mateju D, Malinovska L, Nuske E, Poser I, Richter D, Alberti S. 2015. Promiscuous interactions and protein disaggregases determine the material state of stress-inducible RNP granules. eLife 4: e06807.
131. Kuo PH, Chiang CH, Wang YT, Doudeva LG, Yuan HS. 2014. The crystal structure of TDP-43 RRM1-DNA complex reveals the specific recognition for UG-and TG-rich nucleic acids. Nucleic Acids Res 42: 4712-4722.
132. Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, et al. 2009. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323: 1205-1208.
133. Kwon I, Xiang S, Kato M, Wu L, Theodoropoulos P, Wang T, Kim J, Yun J, Xie Y, McKnight SL. 2014. Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells. Science 345: 1139-1145.
134. Kwong LK, Uryu K, Trojanowski JQ, Lee VM. 2008. TDP-43 proteinopathies: Neurodegenerative protein misfolding diseases without amyloidosis. Neurosignals 16: 41-51.
135. Lagier-Tourenne C, Cleveland DW. 2009. Rethinking ALS: The FUS about TDP-43. Cell 136: 1001-1004.
136. 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-R64.
137. Lagier-Tourenne C, Polymenidou M, Hutt KR, Vu AQ, Baughn M, Huelga SC, Clutario KM, Ling SC, Liang TY, Mazur C, et al. 2012. Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs. Nat Neurosci 15: 1488-1497.
138. Lalmansingh AS, Urekar CJ, Reddi PP. 2011. TDP-43 is a transcriptional repressor: The testis-specific mouse acrv1 gene is a TDP-43 target in vivo. J Biol Chem 286: 10970-10982.
139. Lashuel HA, Hartley D, Petre BM, Walz T, Lansbury PT Jr. 2002. Neurodegenerative disease: Amyloid pores from pathogenic mutations. Nature 418: 291.
140. Lastres-Becker I, Brodesser S, Lutjohann D, Azizov M, Buchmann J, Hintermann E, Sandhoff K, Schurmann A, Nowock J, Auburger G. 2008. Insulin receptor and lipid metabolism pathology in ataxin-2 knock-out mice. Hum Mol Genet 17: 1465-1481.
141. Lattante S, Rouleau GA, Kabashi E. 2013. TARDBPand FUS mutations associated with amyotrophic lateral sclerosis: Summary and update. Hum Mutat 34: 812-826.
142. Lee T, Li YR, Chesi A, Hart MP, Ramos D, Jethava N, Hosangadi D, Epstein J, Hodges B, Bonini NM, et al. 2011a. Evaluating the prevalence of polyglutamine repeat expansions in amyotrophic lateral sclerosis. Neurology 76: 2062-2065.
143. Lee T, Li YR, Ingre C, Weber M, Grehl T, Gredal O, de Carvalho M, Meyer T, Tysnes OB, Auburger G, et al. 2011b. Ataxin-2 intermediate-length polyglutamine expansions in European ALS patients. Hum Mol Genet 20: 1697-1700.
144. Lee EB, Lee VM, Trojanowski JQ. 2012. Gains or losses: Molecular mechanisms of TDP43-mediated neurodegeneration. Nat Rev Neurosci 13: 38-50.
145. Legname G, Baskakov IV, Nguyen HO, Riesner D, Cohen FE, DeArmond SJ, Prusiner SB. 2004. Synthetic mammalian prions. Science 305: 673-676.
146. Li Y, Ray P, Rao EJ, Shi C, Guo W, Chen X, Woodruff EA III, Fushimi K, Wu JY. 2010. A Drosophila model for TDP-43 proteinopathy. Proc Natl Acad Sci 107: 3169-3174.
147. Li YR, King OD, Shorter J, Gitler AD. 2013. Stress granules as crucibles of ALS pathogenesis. J Cell Biol 201: 361-372.
148. Lim L, Wei Y, Lu Y, Song J. 2016. ALS-causing mutations significantly perturb the self-assembly and interaction with nucleic acid of the intrinsically disordered prionlike domain of TDP-43. PLoS Biol 14: e1002338.
149. Lin Y, Protter DS, Rosen MK, Parker R. 2015. Formation and maturation of phase-separated liquid droplets by RNAbinding proteins. Mol Cell 60: 208-219.
150. Ling SC, Albuquerque CP, Han JS, Lagier-Tourenne C, Tokunaga S, Zhou H, Cleveland DW. 2010. ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS. Proc Natl Acad Sci 107: 13318-13323.
151. Ling SC, Polymenidou M, Cleveland DW. 2013. Converging mechanisms in ALS and FTD: Disrupted RNA and protein homeostasis. Neuron 79: 416-438.
152. Ling JP, Pletnikova O, Troncoso JC, Wong PC. 2015. TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD. Science 349: 650-655.
153. Liu-Yesucevitz L, Bilgutay A, Zhang YJ, Vanderweyde T, Citro A, Mehta T, Zaarur N, McKee A, Bowser R, Sherman M, 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.
154. Liu-Yesucevitz L, Bassell GJ, Gitler AD, Hart AC, Klann E, Richter JD, Warren ST, Wolozin B. 2011. Local RNA translation at the synapse and in disease. J Neurosci 31: 16086-16093.
155. Liu-Yesucevitz L, Lin AY, Ebata A, Boon JY, Reid W, Xu YF, Kobrin K, Murphy GJ, Petrucelli L, Wolozin B. 2014. ALS-linked mutations enlarge TDP-43-enriched neuronal RNA granules in the dendritic arbor. J Neurosci 34: 4167-4174.
156. Lorenzetti D, Bohlega S, Zoghbi HY. 1997. The expansion of the CAG repeat in ataxin-2 is a frequent cause of autosomal dominant spinocerebellar ataxia. Neurology 49: 1009-1013.
157. 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.
158. Ludolph AC, Brettschneider J. 2015. TDP-43 in amyotrophic lateral sclerosis—Is it a prion disease? Eur J Neurol 22: 753-761.
159. Luk KC, Kehm V, Carroll J, Zhang B, O’Brien P, Trojanowski JQ, Lee VM. 2012. Pathological a-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338: 949-953.
160. Lukavsky PJ, Daujotyte D, Tollervey JR, Ule J, Stuani C, Buratti E, Baralle FE, Damberger FF, Allain FH. 2013. Molecular basis of UG-rich RNA recognition by the human splicing factor TDP-43. Nat Struct Mol Biol 20: 1443-1449.
161. Mackenzie IR, Neumann M. 2012. FET proteins in frontotemporal dementia and amyotrophic lateral sclerosis. Brain Res 1462: 40-43.
162. Mackenzie IRA, Neumann M. 2017. Fused in sarcoma neuropathology in neurodegenerative disease. Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a024299.
163. Mackenzie IR, Bigio EH, Ince PG, Geser F, Neumann M, Cairns NJ, Kwong LK, Forman MS, Ravits J, Stewart H, et al. 2007. Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. AnnNeurol 61: 427-434.
164. Mackenzie IR, Rademakers R, Neumann M. 2010. TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol 9: 995-1007.
165. Mackenzie IR, Arzberger T, Kremmer E, Troost D, Lorenzl S, Mori K, Weng SM, Haass C, Kretzschmar HA, Edbauer D, et al. 2013. Dipeptide repeat protein pathology in C9ORF72 mutation cases: Clinico-pathological correlations. Acta Neuropathol 126: 859-879.
166. Madsen L, Schulze A, Seeger M, Hartmann-Petersen R. 2007. Ubiquitin domain proteins in disease. BMC Biochem 8: S1.
167. Majumdar A, Cesario WC, White-Grindley E, Jiang H, Ren F, Khan MR, Li L, Choi EM, Kannan K, Guo F, et al. 2012. Critical role of amyloid-like oligomers of Drosophila Orb2 in the persistence of memory. Cell 148: 515-529.
168. Mangus DA, Amrani N, Jacobson A. 1998. Pbp1p, a factor interacting with Saccharomyces cerevisiae poly(A)-binding protein, regulates polyadenylation. Mol Cell Biol 18: 7383-7396.
169. Maniecka Z, Polymenidou M. 2015. From nucleation to widespread propagation: A prion-like concept for ALS. Virus Res 207: 94-105.
170. March ZM, King OD, Shorter J. 2016. Prion-like domains as epigenetic regulators, scaffolds for subcellular organization, and drivers of neurodegenerative disease. Brain Res 1647: 9-18.
171. Mattoo RU, Sharma SK, Priya S, Finka A, Goloubinoff P. 2013. Hsp110 is a bona fide chaperone using ATP to unfold stable misfolded polypeptides and reciprocally collaborate with Hsp70 to solubilize protein aggregates. J Biol Chem 288: 21399-21411.
172. May S, Hornburg D, Schludi MH, Arzberger T, Rentzsch K, Schwenk BM, Grasser FA, Mori K, Kremmer E, Banzhaf-Strathmann J, et al. 2014. C9orf72 FTLD/ALS-associated Gly-Ala dipeptide repeat proteins cause neuronal toxicity and Unc119 sequestration. Acta Neuropathol 128: 485-503.
173. McDonald KK, Aulas A, Destroismaisons L, Pickles S, Beleac E, Camu W, Rouleau GA, Vande Velde C. 2011. TAR DNA-binding protein 43 (TDP-43) regulates stress granule dynamics via differential regulation of G3BPand TIA-1. Hum Mol Genet 20: 1400-1410.
174. Mizielinska S, Gronke S, Niccoli T, Ridler CE, Clayton EL, Devoy A, Moens T, Norona FE, Woollacott IO, Pietrzyk J, et al. 2014. C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science 345: 1192-1194.
175. Molliex A, Temirov J, Lee J, Coughlin M, Kanagaraj AP, Kim HJ, Mittag T, Taylor JP. 2015. Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization. Cell 163: 123-133.
176. Mompean M, Romano V, Pantoja-Uceda D, Stuani C, Baralle FE, Buratti E, Laurents DV. 2016. The TDP-43 Nterminal domain structure at high resolution. FEBS J 283: 1242-1260.
177. Moreno JA, Radford H, Peretti D, Steinert JR, Verity N, Martin MG, Halliday M, Morgan J, Dinsdale D, Ortori CA, et al. 2012. Sustained translational repression by eIF2a-P mediates prion neurodegeneration. Nature 485: 507-511.
178. Moreno JA, Halliday M, Molloy C, Radford H, Verity N, Axten JM, Ortori CA, Willis AE, Fischer PM, Barrett DA, et al. 2013. Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci Transl Med 5: 206ra138.
179. Mori K, Arzberger T, Grasser FA, Gijselinck I, May S, Rentzsch K, Weng SM, Schludi MH, van der Zee J, Cruts M, et al. 2013a. Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins. Acta Neuropathol 126: 881-893.
180. Mori K, Lammich S, Mackenzie IR, Forne I, Zilow S, Kretzschmar H, Edbauer D, Janssens J, Kleinberger G, Cruts M, et al. 2013b. hnRNP A3 binds to GGGGCC repeats and is a constituent of p62-positive/TDP43-negative inclusions in the hippocampus of patients with C9orf72 mutations. Acta Neuropathol 125: 413-423.
181. Mori K, Weng SM, Arzberger T, May S, Rentzsch K, Kremmer E, Schmid B, Kretzschmar HA, Cruts M, Van Broeckhoven C, et al. 2013c. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339: 1335-1338.
182. Mu TW, Ong DS, Wang YJ, Balch WE, Yates JR III, Segatori L, Kelly JW. 2008. Chemical and biological approaches synergize to ameliorate protein-folding diseases. Cell 134: 769-781.
183. Nakashima-Yasuda H, Uryu K, Robinson J, Xie SX, Hurtig H, Duda JE, Arnold SE, Siderowf A, Grossman M, Leverenz JB, et al. 2007. Co-morbidity of TDP-43 proteinopathy in Lewy body related diseases. Acta Neuropathol 114: 221-229.
184. Nencetti S, Rossello A, Orlandini E. 2013. Tafamidis (Vyndaqel): A light for FAP patients. ChemMedChem 8: 1617-1619.
185. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, et al. 2006. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314: 130-133.
186. Neumann M, Kwong LK, Sampathu DM, Trojanowski JQ, Lee VM. 2007. TDP-43 proteinopathy in frontotemporal lobar degeneration and amyotrophic lateral sclerosis: Protein misfolding diseases without amyloidosis. Arch Neurol 64: 1388-1394.
187. Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar HA, Mackenzie IR. 2009. A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 132: 2922-2931.
188. Neumann M, Bentmann E, Dormann D, Jawaid A, DeJesus-Hernandez M, Ansorge O, Roeber S, Kretzschmar HA, Munoz DG, Kusaka H, et al. 2011. FET proteins TAF15 and EWS are selective markers that distinguish FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations. Brain 134: 2595-2609.
189. Nillegoda NB, Kirstein J, Szlachcic A, Berynskyy M, Stank A, Stengel F, Arnsburg K, Gao X, Scior A, Aebersold R, et al. 2015. Crucial HSP70 co-chaperone complex unlocks metazoan protein disaggregation. Nature 524: 247-251.
190. Nishimoto Y, Ito D, Yagi T, Nihei Y, Tsunoda Y, Suzuki N. 2010. Characterization of alternative isoforms and inclusion body of the TAR DNA-binding protein-43. J Biol Chem 285: 608-619.
191. Nonaka T, Hasegawa M. 2017. TDP-43 prions. Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a024463.
192. Nonaka T, Masuda-Suzukake M, Arai T, Hasegawa Y, Akatsu H, Obi T, Yoshida M, Murayama S, Mann DM, Akiyama H, et al. 2013. Prion-like properties of pathological TDP-43 aggregates from diseased brains. Cell Rep 4: 124-134.
193. Ou SH, Wu F, Harrich D, Garcia-Martinez LF, Gaynor RB. 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.
194. Pasinelli P, Brown RH. 2006. Molecular biology of amyotrophic lateral sclerosis: Insights fromgenetics. Nat RevNeurosci 7: 710-723.
195. Paul JW, Gitler AD. 2014. Cell biology. Clogging information flow in ALS. Science 345: 1118-1119.
196. Pesiridis GS, Lee VM, Trojanowski JQ. 2009. Mutations in TDP-43 link glycine-rich domain functions to amyotrophic lateral sclerosis. Hum Mol Genet 18: R156-R162.
197. Pesiridis GS, Tripathy K, Tanik S, Trojanowski JQ, Lee VM. 2011. A “two-hit” hypothesis for inclusion formation by carboxyl-terminal fragments of TDP-43 protein linked to RNA depletion and impaired microtubule-dependent transport. J Biol Chem 286: 18845-18855.
198. Polymenidou M, Cleveland DW. 2011. The seeds of neurodegeneration: Prion-like spreading in ALS. Cell 147: 498-508.
199. Polymenidou M, Cleveland DW. 2012. Prion-like spread of protein aggregates in neurodegeneration. J Exp Med 209: 889-893.
200. Polymenidou M, Lagier-Tourenne C, Hutt KR, Huelga SC, Moran J, Liang TY, Ling SC, Sun E, Wancewicz E, Mazur C, et al. 2011. Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nat Neurosci 14: 459-468.
201. Prusiner SB. 2013. Biology and genetics of prions causing neurodegeneration. Annu Rev Genet 47: 601-623.
202. Pulst SM, Nechiporuk A, Nechiporuk T, Gispert S, Chen XN, Lopes-Cendes I, Pearlman S, Starkman S, Orozco-Diaz G, Lunkes A, et al. 1996. Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet 14: 269-276.
203. Qin H, Lim LZ, Wei Y, Song J. 2014. TDP-43 N terminus encodes a novel ubiquitin-like fold and its unfolded form in equilibrium that can be shifted by binding to ssDNA. Proc Natl Acad Sci 111: 18619-18624.
204. Rademakers R, Stewart H, Dejesus-Hernandez M, Krieger C, Graff-Radford N, Fabros M, Briemberg H, Cashman N, Eisen A, Mackenzie IR. 2010. Fus gene mutations in familial and sporadic amyotrophic lateral sclerosis. Muscle Nerve 42: 170-176.
205. Ramaswami M, Taylor JP, Parker R. 2013. Altered ribostasis: RNA-protein granules in degenerative disorders. Cell 154: 727-736.
206. Rampelt H, Kirstein-Miles J, Nillegoda NB, Chi K, Scholz SR, Morimoto RI, Bukau B. 2012. Metazoan Hsp70 machines use Hsp110 to power protein disaggregation. EMBO J 31: 4221-4235.
207. Ravits JM, La Spada AR. 2009. ALS motor phenotype heterogeneity, focality, and spread: Deconstructing motor neuron degeneration. Neurology 73: 805-811.
208. Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR, Schymick JC, Laaksovirta H, van Swieten JC, Myllykangas L, et al. 2011. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72: 257-268.
209. Renton AE, Chio A, Traynor BJ. 2014. State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci 17: 17-23.
210. Ritson GP, Custer SK, Freibaum BD, Guinto JB, Geffel D, Moore J, Tang W, Winton MJ, Neumann M, Trojanowski JQ, 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.
211. Robberecht W, Philips T. 2013. The changing scene of amyotrophic lateral sclerosis. Nat Rev Neurosci 14: 248-264.
212. Roberts BE, Duennwald ML, Wang H, Chung C, Lopreiato NP, Sweeny EA, Knight MN, Shorter J. 2009. A synergistic small-molecule combination directly eradicates diverse prion strain structures. Nat Chem Biol 5: 936-946.
213. Robinson JL, Geser F, Stieber A, Umoh M, Kwong LK, Van Deerlin VM, Lee VM, Trojanowski JQ. 2013. TDP-43 skeins show properties of amyloid in a subset of ALS cases. Acta Neuropathol 125: 121-131.
214. Rohrer JD, Isaacs AM, Mizielinska S, Mead S, Lashley T, Wray S, Sidle K, Fratta P, Orrell RW, Hardy J, et al. 2015. C9orf72 expansions in frontotemporal dementia and amyotrophic lateral sclerosis. Lancet Neurol 14: 291-301.
215. Romano V, Quadri Z, Baralle FE, Buratti E. 2015. The structural integrity of TDP-43 N-terminus is required for ef-ficient aggregate entrapment and consequent loss of protein function. Prion 9: 1-9.
216. Rotunno MS, Bosco DA. 2013. An emerging role for misfolded wild-type SOD1 in sporadic ALS pathogenesis. Front Cell Neurosci 7: 253.
217. Rowland LP, Shneider NA. 2001. Amyotrophic lateral sclerosis. N Engl J Med 344: 1688-1700.
218. Saini A, Chauhan VS. 2011. Delineation of the core aggregation sequences of TDP-43 C-terminal fragment. Chembiochem 12: 2495-2501.
219. Saini A, Chauhan VS. 2014. Self-assembling properties of peptides derived from TDP-43 C-terminal fragment. Langmuir 30: 3845-3856.
220. Saldi TK, Ash PE, Wilson G, Gonzales P, Garrido-Lecca A, Roberts CM, Dostal V, Gendron TF, Stein LD, Blumenthal T, et al. 2014. TDP-1, the Caenorhabditis elegans ortholog of TDP-43, limits the accumulation of double-stranded RNA. EMBO J 33: 2947-2966.
221. Schmidt HB, Rohatgi R. 2016. In vivo formation of vacuolated multi-phase compartments lacking membranes. Cell Rep 16: 1228-1236.
222. Schmid B, Hruscha A, Hogl S, Banzhaf-Strathmann J, Strecker K, van der Zee J, Teucke M, Eimer S, Hegermann J, Kittelmann M, et al. 2013. Loss of ALS-associated TDP-43 in zebrafish causes muscle degeneration, vascular dysfunction, and reduced motor neuron axon outgrowth. Proc Natl Acad Sci 110: 4986-4991.
223. Schwab C, Arai T, Hasegawa M, Yu S, McGeer PL. 2008. Colocalization of transactivation-responsive DNA-binding protein 43 and huntingtin in inclusions of Huntington disease. J Neuropathol Exp Neurol 67: 1159-1165.
224. Scotter EL, Vance C, Nishimura AL, Lee YB, Chen HJ, Urwin H, Sardone V, Mitchell JC, Rogelj B, Rubinsztein DC, et al. 2014. Differential roles of the ubiquitin proteasome system and autophagy in the clearance of soluble and aggregated TDP-43 species. J Cell Sci 127: 1263-1278.
225. Seelaar H, Schelhaas HJ, Azmani A, Kusters B, Rosso S, Majoor-Krakauer D, de Rijik MC, Rizzu P, ten Brummelhuis M, van Doorn PA, et al. 2007. TDP-43 pathology in familial frontotemporal dementia and motor neuron disease without Progranulin mutations. Brain 130: 1375-1385.
226. Seelaar H, Klijnsma KY, de Koning I, van der Lugt A, Chiu WZ, Azmani A, Rozemuller AJ, van Swieten JC. 2010. Frequency of ubiquitin and FUS-positive, TDP-43-negative frontotemporal lobar degeneration. J Neurol 257: 747-753.
227. Sephton CF, Good SK, Atkin S, Dewey CM, Mayer P III, Herz J, Yu G. 2010. TDP-43 is a developmentally regulated protein essential for early embryonic development. J Biol Chem 285: 6826-6834.
228. Sephton CF, Cenik C, Kucukural A, Dammer EB, Cenik B, Han Y, Dewey CM, Roth FP, Herz J, Peng J, et al. 2011. Identification of neuronal RNA targets of TDP-43-containing ribonucleoprotein complexes. J Biol Chem 286: 1204-1215.
229. Shaw CE. 2010. Capturing VCP: Another molecular piece in the ALS jigsaw puzzle. Neuron 68: 812-814.
230. Shiina Y, Arima K, Tabunoki H, Satoh J. 2010. TDP-43 dimerizes in human cells in culture. Cell Mol Neurobiol 30: 641-652.
231. Shorter J. 2008. Hsp104: Aweapon to combat diverse neurodegenerative disorders. Neurosignals 16: 63-74.
232. Shorter J. 2010. Emergence and natural selection of drugresistant prions. Mol Biosyst 6: 1115-1130.
233. Shorter J. 2011. The mammalian disaggregase machinery: Hsp110 synergizes with Hsp70 and Hsp40 to catalyze protein disaggregation and reactivation in a cell-free system. PLoS ONE 6: e26319.
234. Shorter J. 2016. Engineering therapeutic protein disaggregases. Mol Biol Cell 27: 1556-1560.
235. Shorter J, Lindquist S. 2005. Prions as adaptive conduits of memory and inheritance. Nat Rev Genet 6: 435-450.
236. Shorter J, Taylor JP. 2013. Disease mutations in the prionlike domains of hnRNPA1 and hnRNPA2/B1 introduce potent steric zippers that drive excess RNP granule assembly. Rare Dis 1: e25200.
237. Si K, Giustetto M, Etkin A, Hsu R, Janisiewicz AM, Miniaci MC, Kim JH, Zhu H, Kandel ER. 2003a. A neuronal isoform of CPEB regulates local protein synthesis and stabilizes synapse-specific long-term facilitation in aplysia. Cell 115: 893-904.
238. Si K, Lindquist S, Kandel ER. 2003b. A neuronal isoform of the aplysia CPEB has prion-like properties. Cell 115: 879-891.
239. Si K, Choi YB, White-Grindley E, Majumdar A, Kandel ER. 2010. Aplysia CPEB can form prion-like multimers in sensory neurons that contribute to long-term facilitation. Cell 140: 421-435.
240. Sidrauski C, Acosta-Alvear D, Khoutorsky A, Vedantham P, Hearn BR, Li H, Gamache K, Gallagher CM, Ang KK, Wilson C, et al. 2013. Pharmacological brake-release of mRNA translation enhances cognitive memory. eLife 2: e00498.
241. Sidrauski C, McGeachy AM, Ingolia NT, Walter P. 2015. The small molecule ISRIB reverses the effects of eIF2a phosphorylation on translation and stress granule assembly. eLife 4: e05033.
242. Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, Ackerley S, Durnall JC, Williams KL, Buratti E, et al. 2008. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319: 1668-1672.
243. Stephan JS, Fioriti L, Lamba N, Colnaghi L, Karl K, Derkatch IL, Kandel ER. 2015. The CPEB3 protein is a functional prion that interacts with the actin cytoskeleton. Cell Rep 11: 1772-1785.
244. Sun S, Cleveland DW. 2012. TDP-43 toxicity and the usefulness of junk. Nat Genet 44: 1289-1291.
245. Sun Z, Diaz Z, Fang X, Hart MP, Chesi A, Shorter J, Gitler AD. 2011. Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS. PLoS Biol 9: e1000614.
246. Sun Y, Arslan PE, Won A, Yip CM, Chakrabartty A. 2014. Binding of TDP-43 to the 30UTR of its cognate mRNA enhances its solubility. Biochemistry 53: 5885-5894.
247. Sweeny EA, Jackrel ME, Go MS, Sochor MA, Razzo BM, DeSantis ME, Gupta K, Shorter J. 2015. The hsp104 Nterminal domain enables disaggregase plasticity and potentiation. Mol Cell 57: 836-849.
248. Tan CF, Eguchi H, Tagawa A, Onodera O, Iwasaki T, Tsujino A, Nishizawa M, Kakita A, Takahashi H. 2007. TDP-43 immunoreactivity in neuronal inclusions in familial amyotrophic lateral sclerosis with or without SOD1 gene mutation. Acta Neuropathol 113: 535-542.
249. Tao Z, Wang H, Xia Q, Li K, Li K, Jiang X, Xu G, Wang G, Ying Z. 2015. Nucleolar stress and impaired stress granule formation contribute to C9orf72 RAN translation-induced cytotoxicity. Hum Mol Genet 24: 2426-2441.
250. Thomas MG, Loschi M, Desbats MA, Boccaccio GL. 2011. RNA granules: The good, the bad and the ugly. Cell Signal 23: 324-334.
251. Tollervey JR, Curk T, Rogelj B, Briese M, Cereda M, Kayikci M, Konig J, Hortobagyi T, Nishimura AL, Zupunski V, et al. 2011. Characterizing the RNA targets and positiondependent splicing regulation by TDP-43. Nat Neurosci 14: 452-458.
252. Torrente MP, Shorter J. 2013. The metazoan protein disaggregase and amyloid depolymerase system: Hsp110, Hsp70, Hsp40, and small heat shock proteins. Prion 7: 457-463.
253. Torrente MP, Chuang E, Noll MM, Jackrel ME, Go MS, Shorter J. 2016. Mechanistic insights into Hsp104 potentiation. J Biol Chem 291: 5101-5115.
254. Tran H, Almeida S, Moore J, Gendron TF, Chalasani U, Lu Y, Du X, Nickerson JA, Petrucelli L, Weng Z, 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.
255. Tsai KJ, Yang CH, Fang YH, Cho KH, Chien WL, Wang WT, Wu TW, Lin CP, Fu WM, Shen CK. 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: 1661-1673.
256. Tsaytler P, Harding HP, Ron D, Bertolotti A. 2011. Selective inhibition of a regulatory subunit of protein phosphatase 1 restores proteostasis. Science 332: 91-94.
257. Udan M, Baloh RH. 2011. Implications of the prion-related Q/N domains in TDP-43 and FUS. Prion 5: 1-5.
258. Uryu K, Nakashima-Yasuda H, Forman MS, Kwong LK, Clark CM, Grossman M, Miller BL, Kretzschmar HA, Lee VM, Trojanowski JQ, et al. 2008. Concomitant TAR-DNA-binding protein 43 pathology is present in Alzheimer disease and corticobasal degeneration but not in other tauopathies. J Neuropathol Exp Neurol 67: 555-564.
259. Vaccaro A, Patten SA, Aggad D, Julien C, Maios C, Kabashi E, Drapeau P, Parker JA. 2013. Pharmacological reduction of ER stress protects against TDP-43 neuronal toxicity in vivo. Neurobiol Dis 55: 64-75.
260. Valentine JS, Hart PJ. 2003. Misfolded CuZnSOD and amyotrophic lateral sclerosis. Proc Natl Acad Sci 100: 3617-3622.
261. Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, et al. 2009. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323: 1208-1211.
262. Vieira NM, Naslavsky MS, Licinio L, Kok F, Schlesinger D, Vainzof M, Sanchez N, Kitajima JP, Gal L, Cavacana N, et al. 2014. A defect in the RNA-processing protein HNRPDL causes limb-girdle muscular dystrophy 1G (LGMD1G). Hum Mol Genet 23: 4103-4110.
263. Voigt A, Herholz D, Fiesel FC, Kaur K, Muller D, Karsten P, Weber SS, Kahle PJ, Marquardt T, Schulz JB. 2010. TDP-43-mediated neuron loss in vivo requires RNA-binding activity. PLoS ONE 5: e12247.
264. Wainwright CE, Elborn JS, Ramsey BW, Marigowda G, Huang X, Cipolli M, Colombo C, Davies JC, De Boeck K, Flume PA, et al. 2015. Lumacaftor-Ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med 373: 220-231.
265. Walker AK, Daniels CM, Goldman JE, Trojanowski JQ, Lee VM, Messing A. 2014. Astrocytic TDP-43 pathology in Alexander disease. J Neurosci 34: 6448-6458.
266. Walters RW, Muhlrad D, Garcia J, Parker R. 2015. Differential effects of Ydj1 and Sis1 on Hsp70-mediated clearance of stress granules in Saccharomyces cerevisiae. RNA 21: 1660-1671.
267. Wang F, Wang X, Yuan CG, Ma J. 2010. Generating a prion with bacterially expressed recombinant prion protein. Science 327: 1132-1135.
268. Wang F, Wang X, Ma J. 2011a. Conversion of bacterially expressed recombinant prion protein. Methods 53: 208-213.
269. Wang F, Zhang Z, Wang X, Li J, Zha L, Yuan CG, Weissmann C, Ma J. 2011b. Genetic informational RNA is not required for recombinant prion infectivity. J Virol 86: 1874-1876.
270. Wang IF, Chang HY, Hou SC, Liou GG, Way TD, James Shen CK. 2012. The self-interaction of native TDP-43 C terminus inhibits its degradation and contributes to early proteinopathies. Nat Commun 3: 766.
271. Wang YT, Kuo PH, Chiang CH, Liang JR, Chen YR, Wang S, Shen JC, Yuan HS. 2013. The truncated C-terminal RNA recognition motif of TDP-43 protein plays a key role in forming proteinaceous aggregates. J Biol Chem 288: 9049-9057.
272. Weihl CC, Temiz P, Miller SE, Watts G, Smith C, Forman M, Hanson PI, Kimonis V, Pestronk A. 2008. TDP-43 accumulation in inclusion body myopathy muscle suggests a common pathogenic mechanism with frontotemporal dementia. J Neurol Neurosurg Psychiatry 79: 1186-1189.
273. Wen X, Tan W, Westergard T, Krishnamurthy K, Markandaiah SS, Shi Y, Lin S, Shneider NA, Monaghan J, Pandey UB, et al. 2014. Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death. Neuron 84: 1213-1225.
274. Winton MJ, Igaz LM, Wong MM, Kwong LK, Trojanowski JQ, Lee VM. 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.
275. 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: 27335-27344.
276. Xu YF, Gendron TF, Zhang YJ, Lin WL, D’Alton S, Sheng H, Casey MC, Tong J, Knight J, Yu X, 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.
277. Yang C, Tan W, Whittle C, Qiu L, Cao L, Akbarian S, Xu Z. 2010. The C-terminal TDP-43 fragments have a high aggregation propensity and harm neurons by a dominant-negative mechanism. PLoS ONE 5: e15878.
278. Yu Z, Zhu Y, Chen-Plotkin AS, Clay-Falcone D, McCluskey L, Elman L, Kalb RG, Trojanowski JQ, Lee VM, Van Deerlin VM, et al. 2011. PolyQ repeat expansions in ATXN2 associated with ALS are CAA interrupted repeats. PLoS ONE 6: e17951.
279. Zhang YJ, Xu YF, Cook C, Gendron TF, Roettges P, Link CD, Lin WL, Tong J, Castanedes-Casey M, Ash P, et al. 2009. Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity. Proc Natl Acad Sci 106: 7607-7612.
280. Zhang T, Mullane PC, Periz G, Wang J. 2011. TDP-43 neurotoxicity and protein aggregation modulated by heat shock factor and insulin/IGF-1 signaling. Hum Mol Genet 20: 1952-1965.
281. Zhang T, Hwang HY, Hao H, Talbot C Jr, Wang J. 2012. Caenorhabditis elegans RNA-processing protein TDP-1 regulates protein homeostasis and life span. J Biol Chem 287: 8371-8382.
282. Zhang YJ, Caulfield T, Xu YF, Gendron TF, Hubbard J, Stetler C, Sasaguri H, Whitelaw EC, Cai S, Lee WC, et al. 2013. The dual functions of the extreme N-terminus of TDP-43 in regulating its biological activity and inclusion formation. Hum Mol Genet 22: 3112-3122.
283. Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P, Daley EL, Miller SJ, Cunningham KM, Vidensky S, et al. 2015. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525: 56-61.
284. Zinman L, Cudkowicz M. 2011. Emerging targets and treatments in amyotrophic lateral sclerosis. Lancet Neurol 10: 481-490.
285. Zu T, Gibbens B, Doty NS, Gomes-Pereira M, Huguet A, Stone MD, Margolis J, Peterson M, Markowski TW, Ingram MA, et al. 2011. Non-ATG-initiated translation directed by microsatellite expansions. Proc Natl Acad Sci 108: 260-265.
286. Zu T, Liu Y, Banez-Coronel M, Reid T, Pletnikova O, Lewis J, Miller TM, Harms MB, Falchook AE, Subramony SH, et al. 2013. RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proc Natl Acad Sci 110: E4968-E4977.