BRAIN and NERVE－神経研究の進歩69巻8号

2017年08月発行

特集 遺伝性脊髄小脳失調症の病態と治療展望

ポリグルタミン病の病態機序

著者： 髙橋祐二¹

所属機関： ¹国立精神・神経医療研究センター病院神経内科

ページ範囲：P.901 - P.912

文献概要

ポリグルタミン病は機能獲得型変異を呈する。伸長ポリグルタミン鎖を有する蛋白質の立体構造が変化して凝集体形成をきたす。モノマーやオリゴマーの中間生成物が毒性が高いと考えられている。病態機序として，蛋白質品質管理の障害，遺伝子転写異常，カルシウムホメオスタシスの乱れ，細胞骨格／軸索輸送障害，ミトコンドリア機能障害，RNA代謝異常などが提唱されている。このような病態機序に基づいた治療研究が積極的に推進されている。

参考文献

1)Orr HT, Chung MY, Banfi S, Kwiatkowski TJ Jr, Servadio A, et al: Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet 4: 221-226, 1993

2)Sequeiros J, Seneca S, Martindale J: Consensus and controversies in best practices for molecular genetic testing of spinocerebellar ataxias. Eur J Hum Genet 18: 1188-1195, 2010

3)Takahashi Y, Kanai M, Taminato T, Watanabe S, Matsumoto C, et al: Compound heterozygous intermediate MJD alleles cause cerebellar ataxia with sensory neuropathy. Neurol Genet 3: e123, 2016

4)Tsuji S, Onodera O, Goto J, Nishizawa M; Study Group on Ataxic Diseases: Sporadic ataxias in Japan: a population-based epidemiological study. Cerebellum 7: 189-197, 2008

5)Schuler-Faccini L, Osorio CM, Romariz F, Paneque M, Sequeiros J, et al: Genetic counseling and presymptomatic testing programs for Machado-Joseph Disease: lessons from Brazil and Portugal. Genet Mol Biol 37(1 Suppl): 263-270, 2014

6)Rüb U, Schöls L, Paulson H, Auburger G, Kermer P, et al: Clinical features, neurogenetics and neuropathology of the polyglutamine spinocerebellar ataxias type 1, 2, 3, 6 and 7. Prog Neurobiol 104: 38-66, 2013

calcium channel preferentially aggregates in the cytoplasm of human spinocerebellar ataxia type 6 Purkinje cells. Acta Neuropathol 119: 447-464, 2010

8)Kuemmerle S, Gutekunst CA, Klein AM, Li XJ, Li SH, et al: Huntington aggregates may not predict neuronal death in Huntington's disease. Ann Neurol 46: 842-849, 1999

9)Nagai Y, Popiel HA: Conformational changes and aggregation of expanded polyglutamine proteins as therapeutic targets of the polyglutamine diseases: exposed beta-sheet hypothesis. Curr Pharm Des 14: 3267-3279, 2008

10)Chen S, Berthelier V, Yang W, Wetzel R: Polyglutamine aggregation behavior in vitro supports a recruitment mechanism of cytotoxicity. J Mol Biol 311: 173-182, 2001

11)Klement IA, Skinner PJ, Kaytor MD, Yi H, Hersch SM, et al: Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice. Cell 95: 41-53, 1998

12)Saudou F, Finkbeiner S, Devys D, Greenberg ME: Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95: 55-66, 1998

13)Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S: Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431: 805-810, 2004

14)Takahashi T, Kikuchi S, Katada S, Nagai Y, Nishizawa M, et al: Soluble polyglutamine oligomers formed prior to inclusion body formation are cytotoxic. Hum Mol Genet 17: 345-356, 2008

15)Takahashi T, Katada S, Onodera O: Polyglutamine diseases: where does toxicity come from? what is toxicity? where are we going? J Mol Cell Biol 2: 180-191, 2010

16)Nagai Y, Inui T, Popiel HA, Fujikake N, Hasegawa K, et al: A toxic monomeric conformer of the polyglutamine protein. Nat Struct Mol Biol 14: 332-340, 2007

17)Legleiter J, Mitchell E, Lotz GP, Sapp E, Ng C, et al: Mutant huntingtin fragments form oligomers in a polyglutamine length-dependent manner in vitro and in vivo. J Biol Chem 285: 14777-14790, 2010

18)Nekooki-Machida Y, Kurosawa M, Nukina N, Ito K, Oda T, et al: Distinct conformations of in vitro and in vivo amyloids of huntingtin-exon1 show different cytotoxicity. ProcNatl Acad Sci U S A 106: 9679-9684, 2009

19)Weber JJ, Sowa AS, Binder T, Hübener J: From pathways to targets: understanding the mechanisms behind polyglutamine disease. Biomed Res Int 2014: 701758, 2014［doi: 10.1155/2014/701758］

20)Wellington CL, Hayden MR: Of molecular interactions, mice and mechanisms: new insights into Huntington's disease. Curr Opin Neurol 10: 291-298, 1997

21)Goti D, Katzen SM, Mez J, Kurtis N, Kiluk J, et al: A mutant ataxin-3 putative-cleavage fragment in brains of Machado-Joseph disease patients and transgenic mice is cytotoxic above a critical concentration. J Neurosci 24: 10266-10279, 2004

22)Wellington CL, Ellerby LM, Hackam AS, Margolis RL, Trifiro MA, et al: Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract. J Biol Chem 273: 9158-9167, 1998

23)Liman J, Deeg S, Voigt A, Voßfeldt H, Dohm CP, et al: CDK5 protects from caspase-induced Ataxin-3 cleavage and neurodegeneration. J Neurochem 129: 1013-1023, 2014

24)Koch P, Breuer P, Peitz M, Jungverdorben J, Kesavan J, et al: Excitation-induced ataxin-3 aggregation in neurons from patients with Machado-Joseph disease. Nature 480: 543-546, 2011

25)Haacke A, Hartl FU, Breuer P: Calpain inhibition is sufficient to suppress aggregation of polyglutamine-expanded ataxin-3. J Biol Chem 282: 18851-18856, 2007

26)Hübener J, Weber JJ, Richter C, Honold L, Weiss A, et al: Calpain-mediated ataxin-3 cleavage in the molecular pathogenesis of spinocerebellar ataxia type 3 (SCA3). Hum Mol Genet 22: 508-518, 2013

27)Chai Y, Koppenhafer SL, Bonini NM, Paulson HL: Analysis of the role of heat shock protein (Hsp) molecular chaperones in polyglutamine disease. J Neurosci 19: 10338-10347, 1999

28)Duennwald ML: Cellular stress responses in protein misfolding diseases. Future Sci OA 1: FSO42, 2015［doi: 10.4155/fso.15.42］

29)Malhotra JD, Kaufman RJ: The endoplasmic reticulum and the unfolded protein response. Semin Cell Dev Biol 18: 716-731, 2007

30)Vidal RL, Hetz C: Crosstalk between the UPR and autophagy pathway contributes to handling cellular stress in neurodegenerative disease. Autophagy 8: 970-972, 2012

31)Nath SR, Lieberman AP: The ubiquitination, disaggregation and proteasomal degradation machineries in polyglutamine disease. Front Mol Neurosci 10: 78, 2017

32)Shi CH, Schisler JC, Rubel CE, Tan S, Song B, et al: Ataxia and hypogonadism caused by the loss of ubiquitin ligase activity of the U box protein CHIP. Hum Mol Genet 23: 1013-1024, 2014

33)Jana NR, Dikshit P, Goswami A, Kotliarova S, Murata S, et al: Co-chaperone CHIP associates with expanded polyglutamine protein and promotes their degradation by proteasomes. J Biolo Chem 280: 11635-11640, 2005

34)Bilen J, Bonini NM: Genome-wide screen for modifiers of ataxin-3 neurodegeneration in Drosophila. PLOS Genet 3: 1950-1964, 2007

35)Okazawa H: Polyglutamine diseases: a transcription disorder? Cell Mol Life Sci 60: 1427-1439, 2003

36)Riley BE, Orr HT: Polyglutamine neurodegenerative diseases and regulation of transcription: assembling the puzzle. Genes Dev 20: 2183-2192, 2006

37)Shimohata T, Onodera O, Tsuji S: Interaction of expanded polyglutamine stretches with nuclear transcription factors leads to aberrant transcriptional regulation in polyglutamine diseases. Neuropathology 20: 326-333, 2000

38)Shimohata T, Nakajima T, Yamada M, Uchida C, Onodera O, et al: Expanded polyglutamine stretches interact with TAFⅡ130, interfering with CREB-dependent transcription. Nat Genet 26: 29-36, 2000

39)Suzuki K, Zhou J, Sato T, Takao K, Miyagawa T, et al: DRPLA transgenic mouse substrains carrying single copy of full-length mutant human DRPLA gene with variable sizes of expanded CAG repeats exhibit CAG repeat length- and age-dependent changes in behavioral abnormalities and gene expression profiles. Neurobiol Dis 46: 336-350, 2012

40)Matilla-Dueñas A, Ashizawa T, Brice A, Magri S, McFarland KN, et al: Consensus paper: pathological mechanisms underlying neurodegeneration in spinocerebellar ataxias. Cerebellum 13: 269-302, 2014

41)McCullough SD, Grant PA: Histone acetylation, acetyltransferases, and ataxia: alteration of histone acetylation and chromatin dynamics is implicated in the pathogenesis of polyglutamine-expansion disorders. Adv Protein Chem Struct Biol 79: 165-203, 2010

42)Butler R, Bates GP: Histone deacetylase inhibitors as therapeutics for polyglutamine disorders. Nat Rev Neurosci 7: 784-796, 2006

43)Lin X, Antalffy B, Kang D, Orr HT, Zoghbi HY: Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1. Nat Neurosci 3: 157-163, 2000

44)Liu J, Tang TS, Tu H, Nelson O, Herndon E, et al: Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 2. J Neurosci 29: 9148-9162, 2009

45)Giunti P, Mantuano E, Frontali M, Veneziano L: Molecular mechanism of Spinocerebellar Ataxia type 6: glutamine repeat disorder, channelopathy and transcriptional dysregulation. The multifaceted aspects of a single mutation. Front Cell Neurosci 9: 36, 2015

46)Toru S, Murakoshi T, Ishikawa K, Saegusa H, Fujigasaki H, et al: Spinocerebellar ataxia type 6 mutation alters P-type calcium channel function. J Biol Chem 275: 10893-10898, 2000

47)Watase K, Barrett CF, Miyazaki T, Ishiguro T, Ishikawa K, et al: Spinocerebellar ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant CaV2.1 channels. ProcNatl Acad Sci U S A 105: 11987-11992, 2008

48)Saegusa H, Wakamori M, Matsuda Y, Wang J, Mori Y, et al: Properties of human Cav2.1 channel with a spinocerebellar ataxia type 6 mutation expressed in Purkinje cells. Mol Cell Neurosci 34: 261-270, 2007

49)Yue Q, Jen JC, Nelson SF, Baloh RW: Progressive ataxia due to a missense mutation in a calcium-channel gene. Am J Hum Genet 61: 1078-1087, 1997

50)Coutelier M, Blesneac I, Monteil A, Monin ML, Ando K, et al: A recurrent mutation in CACNA1G alters Cav3.1 T-type calcium-channel conduction and causes autosomal-dominant cerebellar ataxia. Am J Hum Genet 97: 726-737, 2015

51)Morino H, Matsuda Y, Muguruma K, Miyamoto R, Ohsawa R, et al: A mutation in the low voltage-gated calcium channel CACNA1G alters the physiological properties of the channel, causing spinocerebellar ataxia. Mol Brain 8: 89, 2015

52)Lee SB, Bagley JA, Lee HY, Jan LY, Jan YN: Pathogenic polyglutamine proteins cause dendrite defects associated with specific actin cytoskeletal alterations in Drosophila. Proc Natl Acad Sci U S A 108: 16795-16800, 2011

53)Satterfield TF, Jackson SM, Pallanck LJ: A drosophila homolog of the polyglutamine disease gene SCA2 is a dosage-sensitive regulator of actin filament formation. Genetics 162: 1687-1702, 2002

54)Hatanaka Y, Watase K, Wada K, Nagai Y: Abnormalities in synaptic dynamics during development in a mouse model of spinocerebellar ataxia type 1. Sci Rep 5: 16102, 2015［doi: 10.1038/srep16102］

55)Konno A, Shuvaev AN, Miyake N, Miyake K, Iizuka A, et al: Mutant ataxin-3 with an abnormally expanded polyglutamine chain disrupts dendritic development and metabotropic glutamate receptor signaling in mouse cerebellar Purkinje cells. Cerebellum 13: 29-41, 2014

56)Gunawardena S, Goldstein LS: Polyglutamine diseases and transport problems: deadly traffic jams on neuronal highways. Arch Neurol 62: 46-51, 2005

57)Seidel K, den Dunnen WF, Schultz C, Paulson H, Frank S, et al: Axonal inclusions in spinocerebellar ataxia type 3. Acta Neuropathol 120: 449-460, 2010

58)Gunawardena S, Her LS, Brusch RG, Laymon RA, Niesman IR, et al: Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in drosophila. Neuron 40: 25-40, 2003

59)DiMauro S, Schon EA: Mitochondrial disorders in the nervous system. Annu Rev Neurosci 31: 91-123, 2008

60)Laço MN, Oliveira CR, Paulson HL, Rego AC: Compromised mitochondrial complex Ⅱ in models of Machado-Joseph disease. Biochim Biophys Acta 1822: 139-149, 2012

61)Hsu JY, Jhang YL, Cheng PH, Chang YF, Mao SH, et al: The truncated C-terminal fragment of mutant ATXN3 disrupts mitochondria dynamics in spinocerebellar ataxia type 3 models. Front Mol Neurosci 10: 196, 2017［doi: 10.3389/fnmol.2017.00196］

62)Lipinski MM, Yuan J: Mechanisms of cell death in polyglutamine expansion diseases. Curr Opin Pharmacol 4: 85-90, 2004

. Neurobiol Dis 21: 333-345, 2006

. Cell Signal 18: 541-552, 2006

65)Ito H, Fujita K, Tagawa K, Chen X, Homma H, et al: HMGB1 facilitates repair of mitochondrial DNA damage and extends the lifespan of mutant ataxin-1 knock-in mice. EMBO Mol Med 7: 78-101, 2015

66)Batra R, Charizanis K, Swanson MS: Partners in crime: bidirectional transcription in unstable microsatellite disease. Hum Mol Genet 19(R1): R77-R82, 2010

67)Li LB, Yu Z, Teng X, Bonini NM: RNA toxicity is a component of ataxin-3 degeneration in Drosophila. Nature 453: 1107-1111, 2008

68)Nalavade R, Griesche N, Ryan DP, Hildebrand S, Krauß S: Mechanisms of RNA-induced toxicity in CAG repeat disorders. Cell Death Dis 4: e752［doi: 10.1038/cddis.2013.276］

69)Mohan RD, Abmayr SM, Workman JL: The expanding role for chromatin and transcription in polyglutamine disease. Curr Opin Genet Dev 26: 96-104, 2014

70)Jain A, Vale RD: RNA phase transitions in repeat expansion disorders. Nature 546: 243-247, 2017

71)Li L, Matsui M, Corey DR: Activating frataxin expression by repeat-targeted nucleic acids. Nat Commun 7: 10606, 2016［doi: 10.1038/ncomms10606］

72)Scoles DR, Meera P, Schneider MD, Paul S, Dansithong W, et al: Antisense oligonucleotide therapy for spinocerebellar ataxia type 2. Nature 544: 362-366, 2017

73)Moore LR, Rajpal G, Dillingham IT, Qutob M, Blumenstein KG, et al: Evaluation of antisense oligonucleotides targeting ATXN3 in SCA3 mouse models. Mol Ther Nucleic Acids 7: 200-210, 2017

74)Yang S, Chang R, Yang H, Zhao T, Hong Y, et al: CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of Huntington's disease. J Clin Invest 127: 2719-2724, 2017

75)Popiel HA, Takeuchi T, Burke JR, Strittmatter WJ, Toda T, et al: Inhibition of protein misfolding/aggregation using polyglutamine binding peptide QBP1 as a therapy for the polyglutamine diseases. Neurotherapeutics 10: 440-446, 2013

76)Katsuno M, Banno H, Suzuki K, Takeuchi Y, Kawashima M, et al: Efficacy and safety of leuprorelin in patients with spinal and bulbar muscular atrophy (JASMITT study): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol 9: 875-884, 2010

77)Shimohata M, Shimohata T, Igarashi S, Naruse S, Tsuji S: Interference of CREB-dependent transcriptional activation by expanded polyglutamine stretches: augmentation of transcriptional activation as a potential therapeutic strategy for polyglutamine diseases. J Neurochem 93: 654-663, 2005

78)Chou AH, Chen SY, Yeh TH, Weng YH, Wang HL: HDAC inhibitor sodium butyrate reverses transcriptional downregulation and ameliorates ataxic symptoms in a transgenic mouse model of SCA3. Neurobiol Dis 41: 481-488, 2011

79)Stucki DM, Ruegsegger C, Steiner S, Radecke J, Murphy MP, et al: Mitochondrial impairments contribute to Spinocerebellar ataxia type 1 progression and can be ameliorated by the mitochondria-targeted antioxidant MitoQ. Free Radic Biol Med 97: 427-440, 2016

80)Kasumu AW, Hougaard C, Rode F, Jacobsen TA, Sabatier JM, et al: Selective positive modulator of calcium-activated potassium channels exerts beneficial effects in a mouse model of spinocerebellar ataxia type 2. Chem Biol 19: 1340-1353, 2012

81)Corey DR: Synthetic nucleic acids and treatment of neurological diseases. JAMA Neurol 73: 1238-1242, 2016