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）的蛋白质的错误折叠和聚集会导致大脑中的蛋白质团块，称为路易体，从而导致大脑损伤和帕金森病（PD）。越来越多的证据表明，从PD患者脑中分离的α-syn蛋白可以被组织培养皿或小鼠中的脑细胞吸收。这表明蛋白质可能会扩散，病理可能会扩散。许多基本的问题仍然需要回答，以促进我们对PD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，还是像有些人认为的那样甚至是在肠道中开始的，以及环境因素（包括肠道细菌）如何促成这一过程; 2）α-syn蛋白如何从细胞传播到细胞？3)alpha-syn如何从正常状态转变为疾病状态？4)错误折叠/聚集的α-syn是如何以及通过哪些途径从一个细胞转移和扩散到另一个细胞的？5)遗传学是如何促成病理性α-syn的传播的？6)小分子化合物和生物试剂，如特异性抗体，能否阻断α-syn转移、接种和聚集？我们的联合体具有独特的优势，可以利用每个参与小组开发的尖端技术和互补的多学科方法以及新工具和能力来解决这些重要问题。这些包括蛋白质化学，生物化学和生物物理学，细胞和分子生物学，患者源性干细胞的生成，肠道细菌分析，PD动物模型和成像技术（包括通过实时成像研究细胞）的独特能力的专业知识，以及大脑内部的实时成像。这一联合项目的完成将大大有助于推进我们对α-syn蛋白聚集和扩散如何驱动PD进展的理解。更好地了解这一过程将导致识别新的目标，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蛋白极有可能通过类似的机制传播。因此，我们预计我们的研究结果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.