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

JPND 帕金森病中的α-突触核蛋白病理学传播和寻求新的保护策略

• 批准号: MR/N029453/1
• 负责人: Richard Wade-Martins
• 金额: $ 42.97万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN029453%2F1
• 关键词: JPND; Alpha; synuclein; pathology; propagation

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.

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称为路易体的蛋白质团块，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患者的大脑中分离出来的α -syn蛋白可以在组织培养皿或小鼠的脑细胞中被吸收。这表明蛋白质可能扩散，病理可能扩散。为了进一步了解PD的起源和分子机制，以设计创新的保护策略，许多基本问题仍然需要回答。例如，1)α -syn聚合是如何形成的；它们是从大脑开始的，还是像一些人认为的那样，甚至是从肠道开始的？环境因素，包括肠道细菌，是如何促成这一过程的？2) α -syn蛋白如何在细胞间传播？3) α -syn如何从正常状态转变为疾病状态？4)错误折叠/聚合的α -syn是如何从一个细胞传递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，如特异性抗体，能否阻断α -syn的转移、播种和聚集？我们的联盟具有独特的优势，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。这些专业知识包括蛋白质化学、生物化学和生物物理学、细胞和分子生物学、患者来源干细胞的生成、肠道细菌分析、PD动物模型和成像技术，包括通过活体成像研究细胞，以及大脑内部的活体成像。这一联合项目的完成将极大地促进我们对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确定新的靶点，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，我们预计我们的发现也可能普遍适用于其他神经退行性疾病。

项目成果

Tau-proximity ligation assay reveals extensive previously undetected pathology prior to neurofibrillary tangles in preclinical Alzheimer's disease (accepted 2020)

Tau 邻近连接测定揭示了临床前阿尔茨海默氏病神经原纤维缠结之前广泛的先前未检测到的病理学（2020 年接受）

• 期刊: Acta Neuropathologica Communications
• 影响因子: 7.1
• 作者: Bengoa-Vergniory N

Inhibition of striatal dopamine release by the L-type calcium channel inhibitor isradipine co-varies with risk factors for Parkinson's

L 型钙通道抑制剂伊拉地平对纹状体多巴胺释放的抑制作用与帕金森病的危险因素共同变化

• DOI: 10.1101/2020.07.03.186411
• 发表时间: 2020
• 作者: Brimblecombe K

Tau-proximity ligation assay reveals extensive previously undetected pathology prior to neurofibrillary tangles in preclinical Alzheimer's disease.

• DOI: 10.1186/s40478-020-01117-y
• 发表时间: 2021-01-28
• 期刊: Acta neuropathologica communications
• 影响因子: 7.1
• 作者: Bengoa-Vergniory N;Velentza-Almpani E;Silva AM;Scott C;Vargas-Caballero M;Sastre M;Wade-Martins R;Alegre-Abarrategui J
• 通讯作者: Alegre-Abarrategui J

CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson's disease.

• DOI: 10.1038/s41467-020-18689-x
• 发表时间: 2020-09-28
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Bengoa-Vergniory N;Faggiani E;Ramos-Gonzalez P;Kirkiz E;Connor-Robson N;Brown LV;Siddique I;Li Z;Vingill S;Cioroch M;Cavaliere F;Threlfell S;Roberts B;Schrader T;Klärner FG;Cragg S;Dehay B;Bitan G;Matute C;Bezard E;Wade-Martins R
• 通讯作者: Wade-Martins R

Calcium dysregulation combined with mitochondrial failure and electrophysiological maturity converge in Parkinson's iPSC-dopamine neurons.

• DOI: 10.1016/j.isci.2023.107044
• 发表时间: 2023-07-21
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Beccano-Kelly, Dayne A.;Cherubini, Marta;Mousba, Yassine;Cramb, Kaitlyn M. L.;Giussani, Stefania;Caiazza, Maria Claudia;Rai, Pavandeep;Vingill, Siv;Bengoa-Vergniory, Nora;Ng, Bryan;Corda, Gabriele;Banerjee, Abhirup;Vowles, Jane;Cowley, Sally;Wade-Martins, Richard
• 通讯作者: Wade-Martins, Richard