Prion and non-prion induction mechanisms of alpha-synuclein pathology

a-突触核蛋白脑聚集体的存在是a 一系列神经退行性疾病，包括帕金森病、路易体痴呆 和多系统萎缩，并与疾病的严重程度有关。几项研究表明 这种突触核蛋白病理学可能在疾病进展过程中通过自我模板传播， 神经组织含有聚集的α-突触核蛋白可能是一种风险， 类似朊病毒病的疾病传播。然而，我们最近发现，一个非政府组织- 在中枢神经组织来源的白色物质中富集的突触核蛋白因子足以诱导 可以模拟朊病毒样蛋白α-突触核蛋白包涵体病理学的进行性形成 a-突触核蛋白病理学的传播。这些观察结果表明， 一种可以触发α-突触核蛋白病的未知因子，类似于蛋白X，一种假定的辅助因子 朊病毒病的因素此外，该因子可能在人类疾病中具有致病作用。 为了解决突触核蛋白病是否应该重新分类为 朊病毒疾病并阐明疾病进展所涉及的机制，我们提出 以下目的：1）表征非α-突触核蛋白组分的生物化学性质 可以触发α-突触核蛋白的渐进形成，2）确定α-突触核蛋白是否 聚集体可以真实地表现出经典朊病毒的预期性质，并且3）确定 多发性骨髓瘤患者中枢神经组织的相对朊病毒样传递特性 系统萎缩和路易体痴呆，两种表型独特的α-突触核蛋白病。 这些高度整合的目标将提供重要的机制和生物相关的见解 从含有α-突触核蛋白病的组织传播病理学的机制和风险。

The presence of a-synuclein brain aggregates are a hallmark of a spectrum of neurodegenerative disorders, including Parkinson disease, Lewy body dementia and multiple system atrophy, and are associated with disease severity. Several studies suggest that this a-synuclein pathology may spread during disease progression by a self-templating mechanism and that nervous tissue containing aggregated a-synuclein could be a risk for disease transmission similar to prion disease. However, we recently demonstared that a non-- synuclein factor enriched in central nervous tissue-derived white matter is sufficient to induce the progressive formation of a-synuclein inclusion pathology that can mimic prion-like transmission of a-synuclein pathology. These observations suggest the presence of a yet unidentified factor that can trigger a-synucleinopathy, similar to protein X, a putative auxiliary factor in prionopathies. Furthermore, this factor may have a pathogenic role in human disease. To resolve critical issues at the core of whether synucleinopathies should be re-classified as prion disorders and to elucidate mechanisms involved in disease progression we propose the following aims: 1) characterize the biochemical properties of the non-a-synuclein component that can trigger the progressive formation of a-synuclein, 2) determine whether a-synuclein aggregates can truely exhibit properties expected of classical prions, and 3) determine the relative prion-like transmission properties of central nervous tissue from patients with multiple system atrophy and Lewy body dementia, two phenotypically distinctive a-synucleinopathies. These highly integrated aims will provide important mechanistic and biologically relevant insights into the mechanisms and risk of pathology transmission from tissues containing a-synucleinopathies.