CHU de Québec Research Center, Axe Neurosciences, Quebec City, Canada.
Department of Molecular Medicine, Faculty of Medicine, Université Laval, Quebec City, Canada.
PLoS Biol. 2022 Mar 9;20(3):e3001578. doi: 10.1371/journal.pbio.3001578. eCollection 2022 Mar.
Neurodegenerative disorders refer to a group of diseases commonly associated with abnormal protein accumulation and aggregation in the central nervous system. However, the exact role of protein aggregation in the pathophysiology of these disorders remains unclear. This gap in knowledge is due to the lack of experimental models that allow for the spatiotemporal control of protein aggregation, and the investigation of early dynamic events associated with inclusion formation. Here, we report on the development of a light-inducible protein aggregation (LIPA) system that enables spatiotemporal control of α-synuclein (α-syn) aggregation into insoluble deposits called Lewy bodies (LBs), the pathological hallmark of Parkinson disease (PD) and other proteinopathies. We demonstrate that LIPA-α-syn inclusions mimic key biochemical, biophysical, and ultrastructural features of authentic LBs observed in PD-diseased brains. In vivo, LIPA-α-syn aggregates compromise nigrostriatal transmission, induce neurodegeneration and PD-like motor impairments. Collectively, our findings provide a new tool for the generation, visualization, and dissection of the role of α-syn aggregation in PD.
神经退行性疾病是一组常见的中枢神经系统异常蛋白积累和聚集的疾病。然而，蛋白聚集在这些疾病的病理生理学中的确切作用仍不清楚。这种知识上的差距是由于缺乏能够时空控制蛋白聚集的实验模型，以及对与包涵体形成相关的早期动态事件的研究。在这里，我们报告了一种光诱导蛋白聚集（LIPA）系统的开发，该系统能够时空控制α-突触核蛋白（α-syn）聚集形成不溶性沉积物，称为路易体（LB），这是帕金森病（PD）和其他蛋白病的病理标志。我们证明，LIPA-α-syn 包涵体模拟了在 PD 病变大脑中观察到的真实 LB 的关键生化、生物物理和超微结构特征。在体内，LIPA-α-syn 聚集物损害黑质纹状体传递，诱导神经退行性变和 PD 样运动障碍。总的来说，我们的发现为 PD 中 α-syn 聚集作用的产生、可视化和剖析提供了一种新工具。
