Dopaminergic neurodegeneration induced by Parkinson's disease-linked G2019S LRRK2 is dependent on kinase and GTPase activity
An Phu Tran Nguyen, Elpida Tsika, Kaela Kelly, Nathan Levine, Xi Chen, Andrew B. West, Sylviane Boularand, Pascal Barnéoud, Darren J. Moore
Abstract
Significance Parkinson’s disease (PD)-linked familial mutations in LRRK2 impact its enzymatic activity by commonly increasing kinase activity, either directly within the kinase domain or indirectly via the GTPase domain by impairing GTP hydrolysis. Familial LRRK2 mutations also commonly promote neuronal toxicity in cultured cells, and for the common G2019S mutation, these effects are kinase dependent. The mechanisms underlying familial LRRK2 mutations in animal models are uncertain, due to the general lack of robust phenotypes. Our study demonstrates important roles for kinase and GTPase activities in mediating the neurodegenerative effects of G2019S LRRK2 in rodents, highlighting both as promising therapeutic targets for PD.