BRAIN and NERVE－神経研究の進歩61巻9号

2009年09月発行

総説

多系統萎縮症の神経細胞変性はいかに起こるか？

著者： 吉田眞理¹ 曽根美恵²

所属機関： ¹愛知医科大学加齢医科学研究所 ²名古屋掖済会病院神経内科

ページ範囲：P.1051 - P.1060

文献概要

はじめに

　多系統萎縮症（multiple system atrophy：MSA）はオリーブ橋小脳萎縮症（olivopontocerebellar atrophy：OPCA），線条体黒質変性症（striatonigral degeneration：SND），シャイ・ドレーガー症候群（Shy-Drager syndrome：SDS）を含む成人発症の孤発性神経変性疾患である。

　当初OPCA，SND，SDSは独立した疾患として記載されたが，臨床像や病理学的な病変分布には共通点があることから^1－5），1969年にGrahamとOppennheimerらはこれらの病態を包括してMSAと総称することを提唱した^6－9）。わが国のTakahashiら^10）もほぼ同時期にSDSとOPCAが共通した概念のもとに包括され得る疾患であることを考察している。1989～1990年にPappら^11），Nakazatoら^12）はMSAのオリゴデンドログリアの胞体内に嗜銀性封入体を同定し，OPCA，SND，SDSのサブタイプすべてに共通してglial cytoplasmic inclusion（GCI）が出現することを記載した。さらにその後家族性パーキンソン病（Parkinson disease：PD）の遺伝子異常としてα-synuclein（αSN）が同定され^13），Lewy小体がαSNを構成蛋白とすることに加えて，MSAのGCIの主要な構成蛋白がαSNであることが確認された^14－18）。MSAは現在PD，レヴィー小体型認知症（dementia with Lewy bodies：DLB）と共にsynucleinopathyの代表的な疾患であり，αSN陽性のGCIはMSAの病理診断的指標となっている。

　オリゴデンドログリアの胞体内に形成されるGCIは神経細胞の変性を中心課題としてきたそれまでの考え方に大きな転換を与えた。MSAの病態を考えるうえでGCI形成の機序解明は極めて重要な鍵であり，MSAの神経細胞変性はGCIの形成によって神経細胞が2次的に障害された結果であるという“primary oligodendrogliopathy”という作業仮説は極めて魅力的で説得力に富む^19）。

　一方，“primary oligodendrogliopathy”であるとするとMSAの神経細胞は単純に萎縮消失していくと考えられるかもしれない。しかし，神経細胞の胞体内や核内にも封入体が出現していることはKatoら^20），Pappら^21）によって早くから指摘されていた。本稿ではMSAの病態をこれまでのGCI中心の視点とともに，神経細胞自体の変化に注目した観点から再考してみたい。

参考文献

1) Dejerine J, Thomas A: L'atrophie olivo-ponto-cérébelleuse. Nouvelle Iconographie Salpêtrière 13: 330-370, 1900

2) Shy GM, Drager GA: A neurological syndrome associated with orthostatic hypotension: a clinical-pathologic study. Arch Neurol 2: 511-527, 1960

3) ADAMS RD, VAN BOGAERT L, VANDER EECKEN H: STRIATO-NIGRAL DEGENERATION. J Neuropathol Exp Neurol 23: 584-608, 1964

4) van der Eecken H, Adams RD and van Bogaert L: Striopallidal-nigral degeneration. An hitherto undescribed lesion in paralysis agitans. J Neuropathol Exp Neurol 19: 159-161, 1960

5) Johnson RH, Lee Gde J, Oppenheimer DR, Spalding JM: Autonomic failure with orthostatic hypotension due to intermediolateral column degeneration. A report of two cases with autopsies. Q J Med 35: 276-292, 1966

6) Graham JG, Oppenheimer DR: Orthostatic hypotension and nicotine sensitivity in a case of multiple system atrophy. J Neurol Neurosurg Psychiat 32: 28-34, 1969

7) Bannister R, Oppenheimer DR: Degenerative diseases of the nervous system associated with autonomic failure. Brain 95: 457-474, 1972

8) Spokes EG, Bannister R, Oppenheimer DR: Multiple system atrophy with autonomic failure: clinical, histological and neurochemical observations on four cases. J Neurol Sci 43: 59-82, 1979

9) Oppenheimer DR: Lateral horn cells in progressive autonomic failure. J Neurol Sci 46: 393-404, 1980

10) 高橋昭, 高城晋, 山本耕平, 山田徹, 安藤一也: Shy-Drager症候群―オリーブ橋小脳萎縮症との関連―. 臨床神経9: 121-129, 1969

11) Papp MI, Kahn JE, Lantos PL: Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). J Neurol Sci 94: 79-100, 1989

12) Nakazato Y, Yamazaki H, Hirato J, Ishida Y, Yamaguchi H: Oligodendroglial microtubular tangles in olivopontocerebellar atrophy. J Neuropathol Exp Neurol 49: 521-530, 1990

13) Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, et al: Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 276: 2045-2047, 1997

14) Arima K, Ueda K, Sunohara N, Arakawa K, Hirai S, et al: NACP/alpha-synuclein immunoreactivity in fibrillary components of neuronal and oligodendroglial cytoplasmic inclusions in the pontine nuclei in multiple system atrophy. Acta Neuropathol 96: 439-444, 1998

15) Tu PH, Galvin JE, Baba M, Giasson B, Tomita T, et al: Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble alpha-synuclein. Ann Neurol 44: 415-422, 1998

16) Wakabayashi K, Hayashi S, Kakita A, Yamada M, Toyoshima Y, et al: Accumulation of alpha-synuclein/NACP is a cytopathological feature common to Lewy body disease and multiple system atrophy. Acta Neuropathol 96: 445-452, 1998

17) Gai WP, Power JH, Blumbergs PC, Blessing WW: Multiple-system atrophy: a new alpha-synuclein disease? Lancet 352: 547-548, 1998

18) Spillantini MG, Crowther RA, Jakes R, Cairns NJ, Lantos PL, et al: Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson's disease and dementia with Lewy bodies. Neurosci Lett 251: 205-208, 1998

19) Wenning GK, Stefanova N, Jellinger KA, Poewe W, Schlossmacher MG: Multiple system atrophy: a primary oligodendrogliopathy. Ann Neurol 64: 239-246, 2008

20) Kato S, Nakamura H: Cytoplasmic argyrophilic inclusions in neurons of pontine nuclei in patients with olivopontocerebellar atrophy: immunohistochemical and ultrastructural studies. Acta Neuropathol 79: 584-594, 1990

21) Papp MI, Lantos PL: Accumulation of tubular structures in oligodendroglial and neuronal cells as the basic alteration in multiple system atrophy. J Neurol Sci 107: 172-182, 1992

22) Gilman S, Low PA, Quinn N, Albanese A, Ben-Shlomo Y, et al: Consensus statement on the diagnosis of multiple system atrophy. J Auton Nerv Syst 74: 189-192, 1998

23) Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, et al: Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71: 670-676, 2008

24) 陸　重雄, 橋詰良夫: Multiple system atrophyの臨床病理学的研究　線条体・黒質病変の特徴と錐体路・前角障害の分析. 臨床神経24: 552-561, 1984

25) Sobue G, Hashizume Y, Mitsuma T, Takahashi A: Size-dependent myelinated fiber loss in the corticospinal tract in Shy-Drager syndrome and amyotrophic lateral sclerosis. Neurology 37: 529-532, 1987

26) Sobue G, Terao S, Kachi T, et al: Somatic motor efferents in multiple system atrophy with autonomic failure: a clinico-pathological study. J Neurol Sci 112: 113-125, 1992

27) Wakabayashi K, Ikeuchi T, Ishikawa A, Takahashi H: Multiple system atrophy with severe involvement of the motor cortical areas and cerebral white matter. J Neurol Sci 156: 114-117, 1998

28) Terao S, Sobue G, Hashizume Y, Mitsuma T, Takahashi A: Disease-specific patterns of neuronal loss in the spinal ventral horn in amyotrophic lateral sclerosis, multiple system atrophy and X-linked recessive bulbospinal neuronopathy, with special reference to the loss of small neurons in the intermediate zone. J Neurol 241: 196-203, 1994

29) Yoshida M: Multiple system atrophy: α-synuclein and neuronal degeneration. Neuropathology 27: 484-493, 2007

30) Jellinger KA, Seppi K, Wenning GK: Grading of neuropathology in multiple system atrophy: proposal for a novel scale. Mov Disord 20 (Suppl 12): S29-36, 2005

31) Ozawa T, Paviour D, Quinn NP, Josephs KA, Sangha H, et al: The spectrum of pathological involvement of the striatonigral and olivopontocerebellar systems in multiple system atrophy: clinicopathological correlations. Brain 127(Pt 12): 2657-2671, 2004

32) Watanabe H, Saito Y, Terao S, Ando T, Kachi T, et al: Progression and prognosis in multiple system atrophy: an analysis of 230 Japanese patients. Brain 125: 1070-1083, 2002

33) Wenning GK, Quinn N, Magalhaăes M, Mathias C, Daniel SE: "Minimal change" multiple system atrophy. Mov Disord 9: 161-166, 1994

34) Wakabayashi K, Mori F, Nishie M, Oyama Y, Kurihara A, et al: An autopsy case of early ("minimal change") olivopontocerebellar atrophy (multiple system atrophy-cerebellar). Acta Neuropathol 110: 185-190, 2005

35) Sone M, Yoshida M, Hashizume Y, Sobue G. Neuropathological features and a quantitative analysis of neuronal cytoplasmic and neuronal nuclear inclusions in the potine nucleus of multiple system atrophy. Neuropathology 25: A37, 2005

36) Nishie M, Mori F, Yoshimoto M, Takahashi H, Wakabayashi K: A quantitative investigation of neuronal cytoplasmic and intranuclear inclusions in the pontine and inferior olivary nuclei in multiple system atrophy. Neuropathol Appl Neurobiol 30: 546-554, 2004

37) Galvin JE, Schuck TM, Lee VM, Trojanowski JQ: Differential expression and distribution of alpha-, beta-, and gamma-synuclein in the developing human substantia nigra. Exp Neurol 168: 347-355, 2001

38) Maroteaux L, Campanelli JT, Scheller RH: Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci 8: 2804-2815, 1988

39) Yu S, Li X, Liu G, Han J, Zhang C, et al: Extensive nuclear localization of alpha-synuclein in normal rat brain neurons revealed by a novel monoclonal antibody. Neuroscience 145: 539-555, 2007

40) Schneider BL, Seehus CR, Capowski EE, Aebischer P, Zhang SC, et al: Over-expression of alpha-synuclein in human neural progenitors leads to specific changes in fate and differentiation. Hum Mol Genet 16: 651-666, 2007

41) Monti B, Polazzi E, Batti L, Crochemore C, Virgili M, et al: Alpha-synuclein protects cerebellar granule neurons against 6-hydroxydopamine-induced death. J Neurochem 103: 518-530, 2007

42) Sangchot P, Sharma S, Chetsawang B, Porter J, Govitrapong P, et al: Deferoxamine attenuates iron-induced oxidative stress and prevents mitochondrial aggregation and alpha-synuclein translocation in SK-N-SH cells in culture. Dev Neurosci 24: 143-153, 2002

43) Xu S, Zhou M, Yu S, Cai Y, Zhang A, et al: Oxidative stress induces nuclear translocation of C-terminus of alpha-synuclein in dopaminergic cells. Biochem Biophys Res Commun 342: 330-335, 2006

44) Kontopoulos E, Parvin JD, Feany MB: Alpha-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity. Hum Mol Genet 15: 3012-3023, 2006

45) Richter-Landsberg C, Gorath M, Trojanowski JQ, Lee VM: alpha-synuclein is developmentally expressed in cultured rat brain oligodendrocytes. J Neurosci Res 62: 9-14, 2000

46) Matsuo A, Akiguchi I, Lee GC, McGeer EG, McGeer PL, et al: Myelin degeneration in multiple system atrophy detected by unique antibodies. Am J Pathol 153: 735-744, 1998

47) Takahashi M, Tomizawa K, Ishiguro K, Sato K, Omori A, et al: A novel brain-specific 25 kDa protein (p25) is phosphorylated by a Ser/Thr-Pro kinase (TPK II) from tau protein kinase fractions. FEBS Lett 289: 37-43, 1991

48) Takahashi M, Tomizawa K, Fujita SC, Sato K, Uchida T, et al: A brain-specific protein p25 is localized and associated with oligodendrocytes, neuropil, and fiber-like structures of the CA3 hippocampal region in the rat brain. J Neurochem 60: 228-235, 1993

49) Song YJ, Lundvig DM, Huang Y, Gai WP, Blumbergs PC, et al: p25alpha relocalizes in oligodendroglia from myelin to cytoplasmic inclusions in multiple system atrophy. Am J Pathol 171: 1291-1303, 2007

50) Baker KG, Huang Y, McCann H, Gai WP, Jensen PH, et al: P25alpha immunoreactive but alpha-synuclein immunonegative neuronal inclusions in multiple system atrophy. Acta Neuropathol 111: 193-195, 2006

51) Kragh CL, Lund LB, Febbraro F, Hansen HD, Gai WP, et al: alpha -Synuclein Aggregation and Ser-129 Phosphorylation-Dependent Cell Death in Oligodendroglial Cells. J Biol Chem 284: 10211-10222, 2009

52) Kovács GG, László L, Kovács J, Jensen PH, Lindersson E, et al: Natively unfolded tubulin polymerization promoting protein TPPP/p25 is a common marker of alpha-synucleinopathies. Neurobiol Dis 17: 155-162, 2004

53) Lindersson E, Lundvig D, Petersen C, Madsen P, Nyengaard JR, et al: p25alpha Stimulates alpha-synuclein aggregation and is co-localized with aggregated alpha-synuclein in alpha-synucleinopathies. J Biol Chem 280: 5703-5715, 2005

54) Yazawa I, Giasson BI, Sasaki R, Zhang B, Joyce S, et al: Mouse model of multiple system atrophy alpha-synuclein expression in oligodendrocytes causes glial and neuronal degeneration. Neuron 45: 847-859, 2005

55) Soma H, Yabe I, Takei A, Fujiki N, Yanagihara T, et al: Heredity in multiple system atrophy. J Neurol Sci 240: 107-110, 2006

56) Hara K, Momose Y, Tokiguchi S, Shimohata M, Terajima K, et al: Multiplex families with multiple system atrophy. Arch Neurol 64: 545-551, 2007

57) Wullner U, Abele M, Schmitz-Huebsch T, Wilhelm K, Benecke R, et al: Probable multiple system atrophy in a German family. J Neurol Neurosurg Psychiatry 75: 924-925, 2004

58) Wüllner U, Schmitt I, Kammal M, Kretzschmar HA, Neumann M: Definite multiple system atrophy in a German family. J Neurol Neurosurg Psychiatry 80: 449-450, 2009

59) Parkkinen L, Hartikainen P, Alafuzoff I: Abundant glial alpha-synuclein pathology in a case without overt clinical symptoms. Clin Neuropathol 26: 276-283, 2007

60) Fujishiro H, Ahn TB, Frigerio R, DelleDonne A, Josephs KA, et al: Glial cytoplasmic inclusions in neurologically normal elderly: prodromal multiple system atrophy? Acta Neuropathol 116: 269-275, 2008

61) Campbell BC, McLean CA, Culvenor JG, Gai WP, Blumbergs PC, et al: The solubility of alpha-synuclein in multiple system atrophy differs from that of dementia with Lewy bodies and Parkinson's disease. J Neurochem 76: 87-96, 2001

62) Nishie M, Mori F, Fujiwara H, Hasegawa M, Yoshimoto M, et al: Accumulation of phosphorylated alpha-synuclein in the brain and peripheral ganglia of patients with multiple system atrophy. Acta Neuropathol 107: 292-298, 2004

63) Sone M, Yoshida M, Hashizume Y, Hishikawa N, Sobue G: alpha-Synuclein-immunoreactive structure formation is enhanced in sympathetic ganglia of patients with multiple system atrophy. Acta Neuropathol 110: 19-26, 2005

64) 大熊泰之, 服部信孝, 信川文誠, 森秀生, 須田耕一, 他: パーキンソニズムと痴呆を呈し4年の経過で死亡した74歳女性. No To Shinkei 50: 671-682, 1998

65) 下由美, 高梨雅史, 太田聰, 寺嶋一夫, 森秀生, 他: Neurological CPC　母親にパーキンソン病を持ち, パーキンソニズムを呈した56歳女性. No To Shinkei 53: 495-505, 2001