G2019S Mutation of LRRK2 Increases Autophagy via MEK/ERK Pathway

Abstract Parkinson’s disease (PD) is a neurodegenerative disorder characterized by mitochondrial dysfunction, oxidative stress, and later neuronal death. Several genetics and environmental factors have been implicated in the {PD} pathogenesis. Mutations in leucine-rich repeat kinase 2 (LRRK2) are a major cause of familial parkinsonism, and the {G2019S} mutation of {LRRK2} is one of the most prevalent. The deregulation of autophagic process in nerve cells is thought to be a possible cause of PD. {G2019S} mutant fibroblasts exhibited higher autophagic activity that can trigger cell death. In this sense, {G2019S} mutant cells displayed increased apoptosis hallmarks and enough susceptibility to MPP+ (1-methyl-4-phenylpyridinium). {G2019S} {LRRK2} heightens the phosphorylation of MAPK/ERK kinases (MEK). The use of 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene (U0126) reduced the enhanced autophagy suggesting that the {G2019S} mutation induces autophagy via MEK/ERK pathway. Further, the inhibition of this exacerbated autophagy reduces the sensitivity remarked in {G2019S} mutant cells