Immunocytochemical studies of NACP/α-synclein mediated neuronal degeneration

• Project/Area Number: 11670972
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Psychiatric science
• Research Institution: Tokyo Metropolitan Organization of Medical Research
• Principal Investigator: ARIMA Kunimasa (2000-2001) Tokyo Institute of Psychiatry, researcher, 東京都精神医学総合研究所, 研究員 (40124482); 有馬 邦正 (1999) 財団法人 東京都医学研究機構, 東京都精神医学総合研究所, 副参事研究員 (20250227)
• Co-Investigator(Kenkyū-buntansha): SHIMOMURA Yuko Tokyo Institute of Psychiatry, researcher, 東京都精神医学総合研究所, 研究員 (70332377) ; UEDA Kenji Tokyo Institute of Psychiatry, researcher, 東京都精神医学総合研究所, 主任研究員 (90261180) ; NAKAMURA Minako Tokyo Institute of Psychiatry, researcher (40124482) ; 中村 美奈子 財団法人 東京都医学研究機構, 東京都精神医学総合研究所, 技術部研究員
• Project Period (FY): 1999 – 2001
• Project Status: Completed (Fiscal Year 2001)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2001: ¥600,000 (Direct Cost: ¥600,000); Fiscal Year 2000: ¥1,100,000 (Direct Cost: ¥1,100,000); Fiscal Year 1999: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: Parkinson's disease / multiple system atrophy / synuclein / NACP / Neuronal death / conformation disease / fibrinogenesis / tau / コンフォーメーション病 / 多系統萎縮症 / 星状膠細胞 / tau / synuclein / filament pathology / Lewy body / neurofibrillary tangles / neuronal death / electron microscopy

Research Abstract

NACP/α-synuclein, a soluble presynaptic protein, undergoes conformational changes and forms filamentous aggregates in neuronal and glial cells in brains with Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). We carried out immunohistochemical, immunofluolescence, and immuno-electron microscopic (EM) investigation to clarify NACP-filament formation, and subsequent intracellular alteration in neuronal and glial cells. Subjects : Brain tissues of patients with PD, DLB, and MSA were examined. Apanel of anti-NACP antibodies was employed. Results :
(1) NACP-immunoreactive dystrophic neurites (Lewy neurites) were frequently observed in the brain stem of PD/DLB. They shared immunohistochemical features with Lewy bodies in neuronal processes. On immuno-EM, dystrophic neurites were composed of random aggregation of NACP-filaments at the center of processes.
(2) Cellular co-localization of NACP and microtubule-associated tau protein were sometimes confirm ed in PD/DLB brains, and therefore its histological classification into four categories was proposed. On immuno-EM, NACP and tau were found to aggregate into two distinctive subsets of filaments in the same neuronal inclusions in PD/DLB.
(3) NACP-filamentous cytoplasmic inclusions were identified in astrocytes in three of 11 MSA brains. These astrocytes contained 12- 15 nm diameter filaments having a fuzzy outer surface, and appeared to undergo cellular degradation.
(4) NACP-filamentous intra-nuclear inclusions were found in neurons and oligodendrocytes in MSA, but not in astrocytes in MSA or neurons or glia in PD/DLB. Conclusions : (1) We consider that dystrophic neurites may interfere axonal transport, and subsequently cause neuronal dysfunction in PD/DLB brains. (2) Aggregation of NACP may collapse the neuronal microtubular system and trigger aggregation and hyper-phosphorylation of tau in PD/DLB brains. (3) Alteration in astrocytic function in the tissue repair process should be considered in addition to well-accepted oligodendroglial and neuronal pathology in MSA.

Research Products

• [Publications] Arima K et al.: "Cellular co-localization of phosphorylated tau-and NAUP/alpha-synuclein-epitopes in Lewy bodies in sporadic Parkinson's disease and in dementia with Lewy bodies. Brain Research 843:53-61"Brain Research. 843. 53-61 (1999)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Arima K et al.: "NACP/alpha-synuclein and tau constitute two distinctive subsets of filaments in the same neuronal inclusions in brains from a family of Parkinsonism and dementia with Lewy bodies : double-immunolabeling fluorescence and electron microscopic studies"Acta Neuropathol. 100. 115-121 (2000)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Saito Y et al.: "The developmental and aging changes of Down's syndrome cell adhesion molecule expression in normal and Down's syndrome brains"Acta Neuropathol. 100. 654-664 (2000)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Arima K et al.: "Two brothers of fronto-temporal dementia and parkinsonism with an N279K missense mutation of the tau gene"Neurol. 54. 1787-1795 (2000)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Alm MA et al.: "Tubulin seeds α-synuclein fibril formation"J Biol Chem. 277. 2112-2117 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Arima K, Hirai S, Sunohara N, Aoto K, Izumiyama Y, Ueda K, Ikeda K, Kawai M: "Cellular co-localization of phosphorylated tau-and NACP/alpha-synuclein-epitopes in Lewy bodies in sporadic Parkinson's disease and in dementia with Lewy bodies."Brain Research. 843. 53-61 (1999)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Arima K, Mizutani T, Alim MA, Tonozuka-Uehara H, Izumiyama Y, Hirai S, Ueda K: "NACP/alpha-synuclein and tau constitute two distinctive subsets of filaments in the same neuronal inclusions in brains from a family of Parkinsonism and dementia with Lewy bodies : double-immunolabeling fluorescence and electron microscopic studies"Acta Neuropathol. 100. 115-121 (2000)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Saito Y, Oka A, Mizuguchi M, Motonaga K, Mori Y, Becker LE, Arima K, Miyauchi J, Takashima S: "The developmental and aging changes of Down's syndrome cell adhesion molecule expression in normal and Down's syndrome brains"Acta Neuropathol. 100. 654-664 (2000)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Arima K, Kowalska A, Hasegawa M, Mukoyama M, Watanabe R, Kawai M, Takahashi K, Iwatsubo T, Tabira T, Sunohara N: "Two brothers of fronto-temporal dementia and parkinsonism with an N279K missense mutation of the tau gene."Neurol. 54. 1787-1795 (2000)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Alim MA, Hossain MS, Arima K, Takeda K, Izumiyama Y, Nakamura M, Kaji H, Shinoda T, Hisanaga S, Ueda K: "Tubulin seeds α-synuclein fibril formation."J Biol Chem. 277. 2112-2117 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Alim MA et al.: "Tubulin seeds α-synuclein fibril formation."J Biol Chem. 277. 2112-2117 (2002)
• [Publications] Arima K et al.: "NACP/α-synuclein and tau constitute two distinctive subsets of filaments in the same neuronal inclusions in brains from a family of parkinsonism and dementia with Lewy bodies : double immunolabeling fluorescence and electron microscopic studies"Acta Neuropathol. 100. 115-121 (2000)
• [Publications] Arima K et al.: "Two brothers with fronto-temporal dementia and parkinsonism with an N279K mutation of the tau gene"Neurology. 54. 1787-1795 (2000)
• [Publications] Arima K. et al.: "Cellular co-localization of phosphorylated tau-and NACP/α-synuclein-epitopes in Lewy bodies in sporadic Parkinson's disease and in dementia with Lewy bodies"Brain Research. 843. 53-61 (1999)
• [Publications] Arima K. et al.: "NACP/α-synuclein and tau constitute two distinctive subsets of filaments in the same neuronal inclusions in brains from a family of Parkinsonism and dementia with Lewy bodies : double-immunolabeling fluorescence and electron microscopic studies"Acta Neuropathologica. (in press). (2000)
• [Publications] Arima K. et al.: "Two brothers of fronto-temporal dementia and parkinsonism with an N279K missense mutation of the tau gene"Neurology. (in press). (2000)