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

共核疾病，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)聚集体聚集在神经元中的路易小体，导致毒性和细胞死亡。全世界有1000多万人受到帕金森病的影响，但治疗选择仍然很少。令人兴奋的是，监管者的工作最近在ASYN的N-末端区域发现了两个短片段(P1和P2)，它们充当推动聚集的“主-控制器”。这些序列的缺失阻止了体外聚集，并保护线虫帕金森病模型免受蛋白毒性。有趣的是，P1区域的单点突变也发生在相关的蛋白γ突触核蛋白(Gsyn)中，它增加了ALS患者队列中的gsyn聚集。该项目将研究P1和P2在体外ASYN和GSYN以及线虫PD和ALS模型中控制聚集的分子机制。通过创建定点突变，我们将确定P1/P2中增强/减少聚集的关键残基，并研究线虫在整个蠕虫衰老过程中多巴胺能神经元和运动神经元以及人类神经细胞系中的聚集和毒性。最后，我们将探索专门针对P1/P2区域的仿射器防止线虫聚集和毒性的能力，并为开发治疗方案提供翻译机会。

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.