Understanding proteotoxicity of alpha- and gamma-synuclein in neuronal C. elegans models of neurodegeneration

了解 α- 和 γ-突触核蛋白在神经元秀丽隐杆线虫神经变性模型中的蛋白质毒性

• 批准号: 2438492
• 金额: --
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2438492
• 关键词: Understanding; proteotoxicity; alpha; gamma; synuclein

Synucleopathies, such as Parkinson's Disease (PD), are neurodegenerative diseases characterised by the accumulation of alpha-synuclein (asyn) aggregates into Lewy Bodies in neurons, leading to toxicity and cell death. PD affects more than 10 million individuals worldwide, yet treatment options remain sparse. Excitingly, the supervisors' work recently identified two short segments (P1 and P2) in the N-terminal region of asyn that act as "master-controllers" driving aggregation. Deletion of these sequences prevents aggregation in vitro and protect C. elegans models of PD against proteotoxicity. Interestingly, a single point mutation in the P1 region also occurs in the related protein gamma synuclein (gsyn), which increases gsyn aggregation in an ALS patient cohort. The project will investigate the molecular mechanism by which P1 and P2 control aggregation in asyn and gsyn in vitro and in C. elegans models of PD and ALS. Creating site-specific mutations we will identify key residues in P1/P2 that enhance/reduce aggregation, and investigate aggregation and toxicity in dopaminergic and motor neurons in C. elegans throughout aging of the worm as well as in human neuronal cell lines. Finally, we will explore the ability of affimers, that specifically target the P1/P2 regions, to prevent aggregation and toxicity in C. elegans and providing a translational opportunity for the development of therapeutic options.

突触核病，例如帕金森病（PD），是一种神经退行性疾病，其特征是α-突触核蛋白（asyn）聚集体积聚到神经元中的路易体中，导致毒性和细胞死亡。PD影响全球超过1000万人，但治疗选择仍然很少。令人兴奋的是，监督者的工作最近确定了asyn的N末端区域中的两个短片段（P1和P2），它们充当驱动聚合的“主控制器”。这些序列的缺失防止体外聚集并保护C。elegans模型的PD对蛋白质毒性。有趣的是，P1区的单点突变也发生在相关蛋白γ突触核蛋白（gsyn）中，这增加了ALS患者队列中的gsyn聚集。本项目将研究P1和P2在体外控制asyn和gsyn聚集以及在C. PD和ALS的elegans模型。建立位点特异性突变，我们将确定P1/P2中增强/减少聚集的关键残基，并研究C.线虫在整个蠕虫衰老过程中以及在人类神经元细胞系中。最后，我们将探索特异性靶向P1/P2区域的寡聚体防止C. elegans和提供一个翻译的机会，为发展的治疗方案。