JPND Alpha-synuclein pathology propagation in Parkinson's disease and quest for novel protective strategies

一种名为α-突触核蛋白(α-syn)的蛋白质错误折叠和聚集会导致大脑中名为路易小体的蛋白质团块，从而对大脑和帕金森病(PD)造成损害。越来越多的证据表明，从帕金森病患者的大脑中分离出的α-SYN蛋白可以被带入组织培养皿中的脑细胞或小鼠体内。这表明，蛋白质可能会传播，病理也可能会传播。许多基本问题仍然需要回答，以促进我们对帕金森病的起源和分子机制的理解，以期设计创新的保护策略。例如，1)α-SYN聚集体是如何形成的；它们是从大脑开始的，还是像一些人认为的那样从肠道开始，以及包括肠道细菌在内的环境因素是如何促进这一过程的；2)α-SYN蛋白是如何从细胞间传播到细胞的？3)α-SYN是如何从正常状态转变为疾病状态的？4)错误折叠/聚集的α-SYN是如何/通过哪条途径(S)从一个细胞运输和传播到另一个细胞的？5)遗传学如何促进病理性α-SYN的传播？6)小分子化合物和生物试剂，如特定的抗体，能否阻止α-SYN的转移、播种和聚集？我们的联盟处于独特的地位，可以利用结合的尖端技术和每个参与小组开发的互补的、多学科的方法和新的工具和能力来解决这些重要问题。这些领域包括在蛋白质化学、生物化学和生物物理学、细胞和分子生物学、患者来源干细胞的生成、肠道细菌分析、帕金森病的动物模型和成像技术(包括通过活成像研究细胞)以及大脑内的活成像方面的独特能力方面的专业知识。这一联合计划的实施将极大地促进我们对阿尔法-SYN蛋白聚集和扩散如何推动PD进展的理解。更好地了解这一过程将导致确定新的目标，并为开发新的治疗和预防干预措施开辟新的途径。此外，与其他神经退行性疾病相关的各种其他错误折叠的蛋白质很可能通过类似的机制传播。因此，我们预计我们的发现也可能普遍适用于其他神经退行性疾病。

Misfolding and aggregation of a protein named alpha-synuclein (alpha-syn) causes protein clumps in the brain called Lewy bodies leading to damage to the brain and Parkinson's disease (PD). Accumulating evidence shows that alpha-syn protein isolated from a PD patient brain may be taken up into brain cells in a tissue culture dish or in a mouse. This suggests that the protein may spread and the pathology may spread. Many fundamental questions still need to be answered in order to advance our understanding of the origin and the molecular mechanisms of PD with a view to design innovative protective strategies. For example, 1) how do alpha-syn aggregates form; do they start in the brain, or perhaps even in the gut as some people think, and how do environmental factors, including gut bacteria, contribute to this process; 2) how does alpha-syn protein spread from cell-to-cell?; 3) how does alpha-syn shift from a normal state to a disease state? 4) how, and through which route(s), is/are misfolded/aggregated alpha-syn transported and spread from one cell to another?; 5) how do genetics contribute to the spread of pathological alpha-syn?; 6) can small molecule compounds and biological reagents, such as specific antibodies, block alpha-syn transfer, seeding and aggregation?Our consortium is uniquely positioned to take advantage of combined cutting-edge technologies and complementary, multidisciplinary approaches and novel tools and capabilities developed in each of the participating groups, to address these important issues. These include expertise in unique capabilities in protein chemistry, biochemistry and biophysics, cell and molecular biology, generation of patient-derived stem cells, gut bacteria analysis, animal models of PD and imaging techniques including to study cells by live imaging, as well as live imaging inside the brain. The fulfillment of this joint program will contribute significantly to advancing our understanding of how alpha-syn protein aggregation and spread drives PD progression. A better understanding of this process will lead to the identification of novel targets and open new paths for the development of novel therapeutic and preventive interventions. Moreover, it is highly likely that various other misfolded proteins associated with other neurodegenerative diseases may spread through similar mechanisms. Therefore, we anticipate that our findings may also be generally applicable to other neurodegenerative diseases.