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

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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.