GTPase function of Leucine rich repeat kinase 2

National Institute On Aging

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Abstract

LRRK2 gene mutations are a common cause of Parkinsons disease. The protein product of the gene has both kinase and GTPase activities. Because there are mutations in both kinase and GTPase domains, we consider that both activities are probably important for pathogenesis of Parkinson's disease. As such, we are trying to understand each activity in turn and how they interact. In the current period, we have been focussed on non-coding variation and LRRK2 expression and activity. We have documented that non-coding variation associated with PD is associated with increased gene expression of LRRK2 in the human brain, specifically in microglia and not in other cell types in the brain. We were able to fully recapitulate this association in IPSC-derived microglia and extend to show that the same relationship holds for protein expression and enzyme activity. Finally, using a series of CRISPR/Cas based editing tools we demonstrated that the lead GWAS SNP is not the functional controlling variant at this locus but rather more distal variants that work through a microglial-specific transcription factor are important in LRRK2 expression.