Table_1_Quantitative proteomic analysis using a mouse model of Lewy body dementia induced by α-synuclein preformed fibrils injection.XLSX

The aggregation of α-synuclein in the nervous system leads to a class of neurodegenerative disorders termed α-synucleinopathies. A form of primary degenerative dementia called Lewy body dementia (LBD) often develops when these aggregations develop into intracellular inclusions called Lewy bodies (LB) and Lewy neurites (LN). Although high frequency of LBD are the leading cause of dementia after Alzheimer's disease (AD), limited information has been discovered about its pathological pathway or diagnostic criteria. In this report, we attempt to address such shortcomings via utilizing a proteomic approach to identify the proteome changes following intrastriatal injection of α-synuclein pre-formed fibril (α-syn PFF). Using mass spectrometry, we have identified a total of 179 proteins that were either up- or down-regulated at different time points, with the four proteins—TPP3, RAB10, CAMK2A, and DYNLL1, displaying the most significant changes throughout the timeframe. Through further examining the modulated proteins with network-based enrichment analyses, we have found that (1) the most significantly associated neurodegenerative pathways were Parkinson's (pV = 3.0e-16) and Huntington's (pV = 1.9e-15) disease, and (2) the majority of molecular functions specific to the pathology only appeared at later time points. While these results do not expose a conclusive biomarker for LBD, they suggest a framework that is potentially applicable to diagnose and differentiate LBD pathology from other forms of dementia by focusing on the cortical proteome changes which occur in a later time span.

神经系统内α-突触核蛋白（α-synuclein）的聚集会引发一类被命名为α-突触核蛋白病（α-synucleinopathies）的神经退行性疾病。原发性退行性痴呆的一种亚型——路易体痴呆（Lewy body dementia, LBD），通常在这类聚集物形成名为路易体（Lewy bodies, LB）和路易神经突（Lewy neurites, LN）的细胞内包涵体时发病。尽管路易体痴呆是仅次于阿尔茨海默病（Alzheimer's disease, AD）的第二大痴呆病因，但目前学界对其病理通路或诊断标准的认知仍较为有限。本研究旨在通过蛋白质组学方法，探究纹状体内注射α-突触核蛋白预形成纤维（α-synuclein pre-formed fibril, α-syn PFF）后的蛋白质组变化，以弥补这一研究短板。我们借助质谱技术共鉴定出179种在不同时间点呈现上调或下调的蛋白质，其中TPP3、RAB10、CAMK2A与DYNLL1这四种蛋白在整个观测周期内的变化最为显著。通过基于网络的富集分析对受调控蛋白进行深入研究后，我们发现：（1）与该病理关联最显著的神经退行性通路为帕金森病（pV = 3.0e-16）与亨廷顿病（pV = 1.9e-15）；（2）与该病理特异性相关的大部分分子功能仅在较晚时间点才得以显现。尽管本研究并未发现可用于路易体痴呆诊断的确定性生物标志物，但研究结果提示了一个潜在的诊断框架：通过关注皮质蛋白质组在较晚时间窗内的变化，可实现路易体痴呆病理与其他类型痴呆的诊断及鉴别。