GTPase function of Leucine rich repeat kinase 2

National Institute On Aging

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Abstract

In the current period, we found that the influence of PD-associated noncoding variation on LRRK2 expression is specifically propagated through microglia and not by other cell types that express LRRK2 in the human brain. We find microglia-specific regulatory chromatin regions that modulate the LRRK2 expression in human frontal cortex and substantia nigra and confirm these results in a human-induced pluripotent stem cell-derived microglia model. We showed, using a large-scale clustered regularly interspaced short palindromic repeats interference (CRISPRi) screen, that a regulatory DNA element containing the single-nucleotide variant rs6581593 influences the LRRK2 expression in microglia. Our study demonstrates that cell type should be considered when evaluating the role of noncoding variation in disease pathogenesis and sheds light on the mechanism underlying the association of the 5' region of LRRK2 with PD risk. Ongoing work in the lab is aimed at extending these observations to other genes associated with Parkinson's disease and replication in larger cohorts. We have also collaborated with the laboratory of Ping Zhang at NCI to look at the structure of the related kinase LRRK1 using cryo-EM approaches. We were able to confirm that mutations designed to affect LRRK1 activity from structural analyses were effective at producing changes in LRRK1 activity in cells, using lysosomal phosphorylated RAB7 as a readout.