Immunocytochemical studies of NACP/α-synclein mediated neuronal degeneration

NACP/α-突触蛋白介导的神经元变性的免疫细胞化学研究

• 批准号: 11670972
• 负责人: ARIMA Kunimasa
• 金额: $ 2.24万
• 依托单位: Tokyo Metropolitan Organization of Medical Research
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670972/
• 关键词: 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

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 … More 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. Less

NACP/α-突触核蛋白是一种可溶性的突触前蛋白，在帕金森病、路易体痴呆和多系统萎缩患者的脑神经细胞和神经胶质细胞中发生构象变化并形成丝状聚集体。我们进行了免疫组织化学、免疫荧光和免疫电子显微镜(EM)研究，以明确NACP细丝的形成，以及随后神经元和神经胶质细胞的细胞内变化。对象：对PD、DLB和MSA患者的脑组织进行检查。使用抗NACP抗体的APANEL。结果：(1)PD/DLB大鼠脑干内NACP免疫反应阳性的营养不良神经突起(Louy突起)较多。它们与神经元突起中的路易小体具有相同的免疫组织化学特征。免疫组织化学显示，营养不良轴突由突起中央的NACP细丝随机聚集而成。(2)NACP和微管相关tau蛋白的细胞共定位有时证实为…更多地存在于PD/DLB脑中，因此提出了将其组织学分类为四类。免疫组化显示，在PD/DLB的同一神经元内，NACP和tau聚集成两个不同的细丝亚群。(3)在11个MSA脑内，有3个星形细胞内存在NACP-丝状胞浆内包涵体。这些星形胶质细胞含有直径12-15 nm的外表面模糊的细丝，可见细胞降解。(4)在MSA的神经元和少突胶质细胞中可见NACP丝状核内包涵体，而在MSA的星形胶质细胞和PD/DLB的神经元或胶质细胞中未见NACP-核内包涵体。结论：(1)我们认为营养不良的轴突可能干扰了PD/DLB脑内轴突的运输，进而导致神经元功能障碍。(2)NACP的聚集可破坏PD/DLB脑内神经元微管系统，引发tau的聚集和过度磷酸化。(3)在MSA中，除了公认的少突胶质细胞和神经元病理改变外，还应考虑组织修复过程中星形胶质细胞功能的改变。较少

项目成果

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)

Arima K 等人：“额颞叶痴呆和帕金森症两兄弟患有 tau 基因 N279K 错义突变”Neurol。

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)

Arima K. 等人：“额颞叶痴呆和帕金森症两兄弟患有 tau 基因 N279K 错义突变”神经病学。

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 bod

Arima K、Mizutani T、Alim MA、Tonozuka-Uehara H、Izumiyama Y、Hirai S、Ueda K：“NACP/α-突触核蛋白和 tau 蛋白在帕金森病家族的大脑中的相同神经元包含物中构成了两个独特的细丝子集，

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 microscop

Arima K 等人：“NACP/α-突触核蛋白和 tau 蛋白在帕金森病和路易体痴呆家族的大脑中的相同神经元内含物中构成了两个独特的细丝子集：双免疫标记荧光和电子显微镜

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)

Arima K 等人：“患有额颞叶痴呆和帕金森症的两兄弟，患有 tau 基因 N279K 突变”神经病学。