LRRK2 and Parkinson's Disease: From Lack of Structure to Gain of Function

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.Work in the laboratory is funded by FEDER, the Spanish Ministry of Economy and Competitiveness (SAF2014-58653-R), the Junta de Andalucia (CTS-6816), the BBVA Foundation and the Michael J. Fox Foundation. B.F. was funded by a Juan de la Cierva Fellowship (MINECO; JCI2010-07703).Peer reviewe