Biophysical determination of the underlying cause of α-Syn oligomer toxicity

摘要 帕金森病(PD)是第二常见的神经退行性疾病， 影响着全世界近500万人。帕金森病与细胞内 α-突触核蛋白的聚集(α-Syn)，这是一种参与脂质调节的小蛋白 新陈代谢和突触小泡运输。越来越多的证据表明 在大脑和血浆中都观察到的血脂谱的变化可以直接 与α-SYN聚集的开始有关。我们假设α-syn的毒性 聚集体由其结构决定，而其结构又受脂质控制 神经细胞膜的组成。我们团队率先开发了一种无标签、 非侵入性和非破坏性的方法，可用于确定结构 单个α-SYN聚合的组织。我们将利用这种创新的生物物理 α-SYN低聚物蛋白质二级结构的成像研究 存在不同的脂类。我们将研究这些低聚物对初级细胞的毒性。 小鼠大脑中脑、纹状体和皮质区的多巴胺能神经元。这 将揭示α-Syn低聚体的结构与其毒性之间的关系。这个 拟议的工作还旨在确定α-Syn寡聚体在多大程度上与不同的 结构对特定的神经元亚群产生毒性作用。

ABSTRACT Parkinson disease (PD) is the second most common neurodegenerative disease that affects nearly 5 millions of people around the world. PD is associated with intracellular aggregation of α-synuclein (α-Syn), a small protein that is involved in the regulation of lipid metabolism and synaptic vesicle trafficking. A growing body of evidence suggests that alterations in lipid profile, which were observed in both brain and plasma, can be directly linked to the onset of α-Syn aggregation. We hypothesize that the toxicity of α-Syn aggregates is determined by their structure, which in turn is controlled by the lipid composition of neuronal membranes. Our group pioneered development of a label-free, non-invasive and non-destructive approach that can be used to determine the structural organization of individual α-Syn aggregates. We will use this innovative biophysical imaging approach to unravel protein secondary structure of α-Syn oligomers grown in the presence of different lipids. We will investigate toxicity of these oligomers on primary dopaminergic neurons from midbrain, striatal, and cortical areas of the mouse brains. This will reveal the relationship between the structure of α-Syn oligomers and their toxicity. The proposed work also aims to determine the extent to which α-Syn oligomers with different structures exert toxic effects to the specific subsets of neurons.