Dopaminergic neurodegeneration induced by Parkinson's disease-linked G2019S LRRK2 is dependent on kinase and GTPase activity

• DOI: 10.1073/pnas.1922184117
• Publication Date: 2020-07-07T00:25:55Z
• Authors: An Phu Tran Nguyen; Elpida Tsika; Kaela Kelly; Nathan Levine; Xi Chen; Andrew B. West; Sylviane Boularand; Pascal Barneoud; Darren J. Moore
• Keywords: LRRK2

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of late-onset, autosomal-dominant familial Parkinson's disease (PD). LRRK2 functions as both a and GTPase, PD-linked mutations known to influence enzymatic activities. While can commonly induce neuronal damage culture models, mechanisms underlying these pathogenic effects remain uncertain. Rodent models containing often lack robust PD-like neurodegenerative phenotypes. Here, we develop preclinical model PD adult rats induced by brain delivery recombinant adenoviral vectors with neuronal-specific expression human harboring G2019S mutation. In this model, induces degeneration substantia nigra dopaminergic neurons, pathological hallmark PD. Introduction stable kinase-inactive mutation or administration selective inhibitor, PF-360, attenuates neurodegeneration LRRK2. Neuroprotection provided pharmacological inhibition is mediated an unusual mechanism involving destabilization protein relative endogenous Our study further demonstrates that LRRK2-induced critically requires normal GTPase activity, hypothesis-testing increase GTP hydrolysis impair GTP-binding activity provide neuroprotection although via distinct mechanisms. Taken together, our data demonstrate vivo dependent on activity. provides rodent LRRK2-linked nominates modulation promising disease-modifying therapeutic targets.