Wild-type LRRK2 but not its mutant attenuates stress-induced cell death via ERK pathway

Leucine-rich repeat kinase 2 (LRRK2) is a recently identified gene that, when Mutated at specific locations, results in the onset of parkinsonian symptoms with clinical features indistinguishable from idiopathic Parkinson's disease. Based on structural and domain analysis, LRRK2 is predicted to function as a stress-responsive protein scaffold mediating the regulation of mitogen activating protein kinase (MAPK) pathways. Consistent with this notion, our results Supported the notion that expression of wild-type LRRK2 but not Y1699C or G2019S mutants enhanced the tolerance of HEK293 and SH-SY5Y cells towards H2O2-induced oxidative stress. This increase in stress tolerance was dependent on the presence of the kinase domain of the LRRK2 gene and manifested through the activation of the ERK pathway. Collectively, out-results indicated that cells expressing LRRK2 Mutants suffer a loss of protection normally derived from wild-type LRRK2, making them more Vulnerable to oxidative stress. Published by Elsevier Inc.