ALPHA-SYNUCLEIN-INDUCED AMYLOIDOSIS

α-突触核蛋白诱导的淀粉样变性

• 批准号: 6919443
• 负责人: JOHN Q. TROJANOWSKI
• 金额: $ 27.64万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6919443
• 关键词: Alzheimer' s disease; Downs syndrome; Lewy body; Parkinson' s disease; alpha synuclein; amyloid proteins; amyloidosis; amyotrophic lateral sclerosis; genetically modified animals; heat shock proteins; human tissue; laboratory mouse; molecular pathology; neural degeneration; neuritic plaques; neurofibrillary tangles; postmortem; progressive supranuclear palsy; protein localization; protein protein interaction; protein quantitation /detection; protein structure; protein structure function; tau proteins; transfection /expression vector

Pathologically altered alpha-synuclein fibrillizes and forms Lewy bodies (LBs) and Lewy neurites in Parkinson's disease (PD) and related disorders referred to as synucleinopathies because alpha-synuclein inclusions are the predominant brain lesions in these diseases. However, similar lesions are abundant in a common subtype of sporadic Alzheimer's disease (AD) known as the LB variant of AD (LBVAD), as well as in familial AD and Down's syndrome, while LBs and Lewy neurites have been reported in some tauopathies such as progressive supranuclear palsy (PSP) and Guam amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC). Moreover, while glial cytoplasmic inclusions (GCIs) in multiple system atrophy (MSA) are composed of fibrillized alpha-synuclein, aggregated tau predominates in a subset of GCIs. Thus, fibrillary deposits of alpha-synuclein, Abeta and tau co-occur in neurodegenerative diseases, and some cells harbor both alpha-synuclein and tau inclusions. Since we showed alpha-synuclein promotes tau fibrillization into homopolymeric filaments, we hypothesize that alpha-synuclein interacts with amyloidogenic tau and Abeta in synucleinopathies to induce their oligomerization and/or fibrillization. Indeed, oligomers of tau and Abeta could contribute to neurodegeneration in synucleinopathies before coalescing into morphologically detectable fibrillar inclusions. Thus, we now propose to test the hypothesis that pathological alpha-synuclein interacts with tau and Abeta to promote their oligomerization, fibrillization and accumulation in synucleinopathy brains while heat shock proteins may mitigate this. The elucidation of mechanisms underlying neurodegenerative brain amyloidoses involving alpha-synuclein, tau and Abeta is essential for the design of more effective therapeutic interventions for synucleinopathies.

在帕金森病 (PD) 和称为突触核蛋白病的相关疾病中，病理改变的 α-突触核蛋白原纤维化并形成路易体 (LB) 和路易神经突，因为 α-突触核蛋白内含物是这些疾病中主要的脑损伤。然而，类似的病变在散发性阿尔茨海默氏病 (AD) 的常见亚型（即 AD 的 LB 变体 (LBVAD)）以及家族性 AD 和唐氏综合症中大量存在，而 LB 和路易神经突已在一些 tau蛋白病中报道，例如如进行性核上性麻痹 (PSP) 和关岛肌萎缩侧索硬化症/帕金森痴呆症 复杂（ALS/PDC）。此外，虽然多系统萎缩 (MSA) 中的胶质细胞质内含物 (GCI) 由纤维化 α-突触核蛋白组成，但聚集的 tau 在 GCI 子集中占主导地位。因此，α-突触核蛋白、Abeta 和 tau 的纤维沉积在神经退行性疾病中同时出现，并且一些细胞同时含有 α-突触核蛋白和 tau 内含物。由于我们证明 α-突触核蛋白促进 tau 原纤维化为均聚丝，因此我们假设 α-突触核蛋白与突触核蛋白病中的淀粉样变性 tau 和 Abeta 相互作用，诱导其寡聚化和/或原纤维化。事实上，tau 和 Abeta 的寡聚物在合并成形态学上可检测到的纤维状包涵体之前可能会导致突触核蛋白病中的神经变性。因此，我们现在建议检验以下假设：病理性 α-突触核蛋白与 tau 和 Abeta 相互作用，促进它们在突触核蛋白病大脑中的寡聚化、原纤维化和积累，而热休克蛋白可能会减轻这种情况。阐明涉及 α-突触核蛋白、tau 和 Abeta 的神经退行性脑淀粉样变性的机制对于设计更有效的突触核蛋白病治疗干预措施至关重要。