The pathogenic effect of LRRK2-G2019S mutation: Impairment of neuronal autophagy in Parkinson’s Disease

富含亮氨酸重复序列激酶2（LRRK 2）基因的G2019 S突变已被确定为散发性和家族性帕金森病的最常见遗传原因。然而，G2019 S突变在帕金森病发展中的致病作用尚不清楚。已知LRRK 2-G2019 S破坏神经元自噬，但其潜在机制仍有待阐明。自噬是衰老细胞器和聚集蛋白质降解和再循环的重要细胞过程。自噬在神经元中尤其重要。在其他方面健康的小鼠中抑制自噬已被证明会诱导神经变性。自噬体在轴突的远端形成，并通过与溶酶体融合逆行运输到途中成熟的细胞索马。因此，轴突运输对于神经元中有效的自噬体清除是必需的。G2019 S突变已显示损害神经元自噬体清除。这种作用可能是通过损害轴突自噬体转运介导的。该项目旨在使用具有G2019 S突变的人类诱导多能干细胞衍生的神经元来研究G2019 S影响自噬体轴突运输的潜在机制，以及有缺陷的运输是否会损害自噬体及其货物的清除。

G2019S mutation of the leucine-rich repeat kinase 2 (LRRK2) gene has been identified as the most frequent genetic cause of sporadic and familial forms of Parkinson’s Disease. However, the pathogenic role of G2019S mutation in the development of Parkinson’s Disease is unclear. It is known that LRRK2-G2019S disrupts neuronal autophagy, but the underlying mechanism remains to be elucidated. Autophagy is an essential cellular process for the degradation and recycling of aging organelles and aggregated proteins. Autophagy is particularly important in neurons. Inhibition of autophagy in otherwise healthy mice has been shown to induce neurodegeneration. Autophagosomes are formed at the distal tip of the axon and transported retrogradely towards the cell soma maturing en-route by fusing with lysosomes. Thus, axonal transport is essential for efficient autophagosome clearance in neurons. G2019S mutation has been shown to impair neuronal autophagosome clearance. This effect may be mediated through impairment of axonal autophagosome transport. The proposed project aims to use human induced pluripotent stem cell-derived neurons with G2019S mutation to investigate the underlying mechanism by which G2019S affects axonal transport of autophagosomes and whether defective transport compromises clearance of autophagosomes and their cargo.