Convergence of LRRK2 and GBA1 in the pathogenesis of PD

Genetic studies in Parkinson’s disease (PD) have led to the discovery of several causal and risk genes, whose mutations lead to pathological forms of this condition. Among those described are mutations in leucine-rich repeat kinase 2 (LRRK2) and GBA1, the gene encoding glucocerebrosidase (GCase). The LRRK2 G2019S mutation is the most common PD mutation, accounting for approximately 3% of familial cases and about 1% of all sporadic cases while mutations in GBA1 are known to be the most common genetic risk factor of PD.. Interestingly, recent genetic studies have uncovered individuals with mutations in both GBA1 and LRRK2 who developed PD symptoms much earlier than the average age at onset of the LRRK2 or GBA1 mutation carriers alone, suggesting a possible synergistic effect of the two variants in disease pathogenesis. While the effects of mutations in LRRK2 and GBA1 have been studied independently, it is not known if/how both genes interact to collectively contribute to PD pathogenesis. An interaction between LRRK2 and GBA1 in a biological pathway may open the door to investigating therapeutic efficacy of LRRK2 kinase inhibitors in the GBA population and GBA-targeted therapies in LRRK2 carriers. Here we propose to use LRRK2 mutant mouse models and human dopaminergic neurons derived from induced pluripotent stem cells (iPSC) to study the effect of LRRK2 mutations or LRRK2 kinase inhibitors on GCase.