BRAIN and NERVE－神経研究の進歩71巻11号

2019年11月発行

増大特集 ALS2019

TDP-43封入体から解くALSの分子病態

著者： 坪口晋太朗¹ 石原智彦¹² 須貝章弘¹ 横関明男³ 小野寺理¹²

所属機関： ¹新潟大学脳研究所臨床神経科学部門神経内科学分野 ²新潟大学脳研究所分子神経疾患資源解析学分野 ³新潟大学大学院医歯学総合研究科臓器連関学寄附講座

ページ範囲：P.1183 - P.1189

文献概要

TDP-43蛋白質の封入体形成機構は，筋萎縮性側索硬化症（ALS）の主要な分子病態機序である。ALS原因遺伝子の機能解析から，TDP-43封入体形成にはストレス顆粒形成，蛋白質分解機構，TDP-43蛋白質の自己調節機構の破綻などが関わることが見出された。これらの解明された分子病態に基づく，ALS治療方法の確立が期待される。

参考文献

1)Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, et al: Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362: 59-62, 1993

2)Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, et al: Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323: 1205-1208, 2009

3)DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer AL, Baker M, et al: Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72: 245-256, 2011

4)Chia R, Chiò A, Traynor BJ: Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications. Lancet Neurol 17: 94-102, 2018

5)Brown RH Jr, Al-Chalabi A: Amyotrophic lateral sclerosis. N Engl J Med 377: 1602, 2017［doi: 10.1056/NEJMc1710379］

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

7)Yokoseki A, Shiga A, Tan CF, Tagawa A, Kaneko H, et al: TDP-43 mutation in familial amyotrophic lateral sclerosis. Ann Neurol 63: 538-542, 2008

8)Gitcho MA, Baloh RH, Chakraverty S, Mayo K, Norton JB, et al: TDP-43 A315T mutation in familial motor neuron disease. Ann Neurol 63: 535-538, 2008

9)Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, et al: TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319: 1668-1672, 2008

10)Vance C, Rogelj B, Hortobágyi T, De Vos KJ, Nishimura AL, et al: Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323: 1208-1211, 2009

11)Konno T, Shiga A, Tsujino A, Sugai A, Kato T, et al: Japanese amyotrophic lateral sclerosis patients with GGGGCC hexanucleotide repeat expansion in C9ORF72. J Neurol Neurosurg Psychiatry 84: 398-401, 2013

12)Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, et al: Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441: 885-889, 2006

13)Ramesh N, Pandey UB: Autophagy dysregulation in ALS: when protein aggregates get out of hand. Front Mol Neurosci 10: 263, 2017［doi: 10.3389/fnmol.2017.00263］

14)Cirulli ET, Lasseigne BN, Petrovski S, Sapp PC, Dion PA, et al: Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science 347: 1436-1441, 2015

15)Jain S, Wheeler JR, Walters RW, Agrawal A, Barsic A, et al: ATPase-modulated stress granules contain a diverse proteome and substructure. Cell 164: 487-498, 2016

16)Liu-Yesucevitz L, Bilgutay A, Zhang YJ, Vanderwyde T, Citro A, et al: Tar DNA binding protein-43 (TDP-43) associates with stress granules: analysis of cultured cells and pathological brain tissue. PLOS ONE 5: e13250, 2010［doi: 10.1371/journal.pone.0013250］

17)Colombrita C, Zennaro E, Fallini C, Weber M, Sommacal A, et al: TDP-43 is recruited to stress granules in conditions of oxidative insult. J Neurochem 111: 1051-1061, 2009

18)Li YR, King OD, Shorter J, Gitler AD: Stress granules as crucibles of ALS pathogenesis. J Cell Biol 201: 361-372, 2013

19)Elden AC, Kim HJ, Hart MP, Chen-Plotkin AS, Johnson BS, et al: Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466: 1069-1075, 2010

20)Mackenzie IR, Nicholson AM, Sarkar M, Messing J, Purice MD, et al: TIA1 mutations in amyotrophic lateral sclerosis and frontotemporal dementia promote phase separation and alter stress granule dynamics. Neuron 95: 808-816, e9, 2017

21)Vogler TO, Wheeler JR, Nguyen ED, Hughes MP, Britson KA, et al: TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle. Nature 563: 508-513, 2018

22)Kato M, Han TW, Xie S, Shi K, Du X, et al: Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels. Cell 149: 753-767, 2012

23)Patel A, Lee HO, Jawerth L, Maharana S, Jahnel M, et al: A liquid-to-solid phase transition of the ALS protein FUS accelerated by disease mutation. Cell 162: 1066-1077, 2015

24)Shin Y, Brangwynne CP: Liquid phase condensation in cell physiology and disease. Science 357, 2017［doi: 10.1126/science.aaf4382］

25)Guenther EL, Cao Q, Trinh H, Lu J, Sawaya MR, et al: Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation. Nat Struct Mol Biol 25: 463-471, 2018

26)Kato M, Lin Y, McKnight SL: Cross-beta polymerization and hydrogel formation by low-complexity sequence proteins. Methods 126: 3-11, 2017

27)Molliex A, Temirov J, Lee J, Coughlin M, Kanagaraj AP, et al: Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization. Cell 163: 123-133, 2015

28)Lee KH, Zhang P, Kim HJ, Mitrea DM, Sarkar M, et al: C9orf72 dipeptide repeats impair the assembly, dynamics, and function of membrane-less organelles. Cell 167: 774-788, e17, 2016

29)Cohen TJ, Lee VM, Trojanowski JQ: TDP-43 functions and pathogenic mechanisms implicated in TDP-43 proteinopathies. Trends Mol Med 17: 659-667, 2011

30)Dormann D, Capell A, Carlson AM, Shankaran SS, Rodde R, et al: Proteolytic processing of TAR DNA binding protein-43 by caspases produces C-terminal fragments with disease defining properties independent of progranulin. J Neurochem 110: 1082-1094, 2009

31)Chen AK, Lin RY, Hsieh EZ, Tu PH, Chen RP, et al: Induction of amyloid fibrils by the C-terminal fragments of TDP-43 in amyotrophic lateral sclerosis. J Am Chem Soc 132: 1186-1187, 2010

32)Jiang LL, Zhao J, Yin XF, He WT, Yang H, et al: Two mutations G335D and Q343R within the amyloidogenic core region of TDP-43 influence its aggregation and inclusion formation. Sci Rep 6: 23928, 2016［doi: 10.1038/srep23928］

33)Li HR, Chiang WC, Chou PC, Wang WJ, Huang JR: TAR DNA-binding protein 43 (TDP-43) liquid-liquid phase separation is mediated by just a few aromatic residues. J Biol Chem 293: 6090-6098, 2018

34)Conicella AE, Zerze GH, Mittal J, Fawzi NL: ALS mutations disrupt phase separation mediated by alpha-helical structure in the TDP-43 low-complexity C-terminal domain. Structure 24: 1537-1549, 2016

35)Sun Y, Chakrabartty A: Phase to phase with TDP-43. Biochemistry 56: 809-823, 2017

36)Weissman AM, Shabek N, Ciechanover A: The predator becomes the prey: regulating the ubiquitin system by ubiquitylation and degradation. Nat Rev Mol Cell Biol 12: 605-620, 2011

37)Saha S, Panigrahi DP, Patil S, Bhutia SK: Autophagy in health and disease: a comprehensive review. Biomed Pharmacother 104: 485-495, 2018

38)Scotter EL, Vance C, Nishimura AL, Lee YB, Chen HJ, et al: 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, 2014

39)Ichimura Y, Kumanomidou T, Sou YS, Mizushima T, Ezaki J, et al: Structural basis for sorting mechanism of p62 in selective autophagy. J Biol Chem 283: 22847-22857, 2008

40)Ying H, Yue BY: Optineurin: the autophagy connection. Exp Eye Res 144: 73-80, 2016

41)Deng HX, Chen W, Hong ST, Boycott KM, Gorrie GH, et al: Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 477: 211-215, 2011

42)Oakes JA, Davies MC, Collins MO: TBK1: a new player in ALS linking autophagy and neuroinflammation. Mol Brain 10: 5, 2017［doi: 10.1186/s13041-017-0287-x］

43)Johnson JO, Mandrioli J, Benatar M, Abramzon Y, Van Deerlin VM, et al: Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68: 857-864, 2010

44)Ju JS, Fuentealba RA, Miller SE, Jackson E, Piwnica-Worms D, et al: Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease. J Cell Biol 187: 875-888, 2009

45)Ederle H, Dormann D: TDP-43 and FUS en route from the nucleus to the cytoplasm. FEBS Lett 591: 1489-1507, 2017

46)Lee EB, Lee VM, Trojanowski JQ: Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration. Nat Rev Neurosci 13: 38-50, 2011

47)Ayala YM, Zago P, D'Ambrogio A, Xu YF, Petrucelli L, et al: Structural determinants of the cellular localization and shuttling of TDP-43. J Cell Sci 121: 3778-3785, 2008

48)Freibaum BD, Chitta RK, High AA, Taylor JP: Global analysis of TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery. J Proteome Res 9: 1104-1120, 2010

49)Higashi S, Kabuta T, Nagai Y, Tsuchiya Y, Akiyama H, et al: TDP-43 associates with stalled ribosomes and contributes to cell survival during cellular stress. J Neurochem 126: 288-300, 2013

50)Ishihara T, Ariizumi Y, Shiga A, Kato T, Tan CF, et al: Decreased number of Gemini of coiled bodies and U12 snRNA level in amyotrophic lateral sclerosis. Hum Mol Genet 22: 4136-4147, 2013

51)Tsuiji H, Iguchi Y, Furuya A, Kataoka A, Hatsuta H, et al: Spliceosome integrity is defective in the motor neuron diseases ALS and SMA. EMBO Mol Med 5: 221-234, 2013

52)Veldink JH, Kalmijn S, Van der Hout AH, Lemmink HH, Groeneveld GJ, et al: SMN genotypes producing less SMN protein increase susceptibility to and severity of sporadic ALS. Neurology 65: 820-825, 2005

53)Will CL, Lührmann R: Spliceosome structure and function. Cold Spring Harb Perspect Biol 3, 2011［doi: 10.1101/cshperspect.a003707］

54)Reber S, Stettler J, Filosa G, Colombo M, Jutzi D, et al: Minor intron splicing is regulated by FUS and affected by ALS-associated FUS mutants. EMBO J 35: 1504-1521, 2016

55)Avendaño-Vázquez SE, Dhir A, Bembich S, Buratti E, Proudfoot N, et al: Autoregulation of TDP-43 mRNA levels involves interplay between transcription, splicing, and alternative polyA site selection. Genes Dev 26: 1679-1684, 2012

56)Koyama A, Sugai A, Kato T, Ishihara T, Shiga A, et al: Increased cytoplasmic TARDBP mRNA in affected spinal motor neurons in ALS caused by abnormal autoregulation of TDP-43. Nucleic Acids Res 44: 5820-5836, 2016

57)Sugai A, Kato T, Koyama A, Koike Y, Kasahara S, et al: Robustness and vulnerability of the autoregulatory system that maintains nuclear TDP-43 levels: a trade-off hypothesis for ALS pathology based on in Silico data. Front Neurosci 12: 28, 2018［doi: 10.3389/fnins.2018.00028］

58)Nussbacher JK, Tabet R, Yeo GW, Lagier-Tourenne C: Disruption of RNA metabolism in neurological diseases and emerging therapeutic interventions. Neuron 102: 294-320, 2019