Mutations in LRRK2 comprise the most common cause for familial Parkinson’s disease (PD),
and variations increase risk for sporadic disease, implicating LRRK2 in the entire disease spectrum.
LRRK2 is a large protein harbouring both GTPase and kinase domains which display measurable catalytic
activity. Most pathogenic mutations increase the kinase activity, with increased activity being cytotoxic
under certain conditions. These findings have spurred great interest in drug development approaches,
and various specific LRRK2 kinase inhibitors have been developed. However, LRRK2 is a
largely ubiquitously expressed protein, and inhibiting its function in some non-neuronal tissues has
raised safety liability issues for kinase inhibitor approaches. Therefore, understanding the cellular and
cell type-specific role(s) of LRRK2 has become of paramount importance. This review will highlight
current knowledge on the precise biochemical activities of normal and pathogenic LRRK2, and highlight
the most common proposed cellular roles so as to gain a better understanding of the cell type-specific
effects of LRRK2 modulators.
Keywords: Autophagy, endocytosis, GTPase, kinase, LRRK2, Parkinson’s disease, Rab7, Rab7L1.
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