Pathogenic LRRK2 R1441C mutation is associated with striatal alterations

Abstract

LRRK2 mutations are associated with both familial and sporadic forms of Parkinsons disease (PD). Convergent evidence suggests that LRRK2 plays critical roles in regulating striatal function. Here, by using knock-in mouse lines that express the two most common LRRK2 pathogenic mutations--G2019S and R1441C--we investigated how pathogenic LRRK2 mutations altered striatal physiology. We found that R1441C mice displayed a reduced nigrostriatal dopamine release and hypoexcitability in indirect-pathway striatal projection neurons. These alterations were associated with an impaired striatal-dependent motor learning. This deficit in motor learning was rescued following the subchronic administration of the LRRK2 kinase inhibitor Mli-2. In contrast, though a decreased release of dopamine was observed in the G2019S knock-in mice no concomitant cellular and behavioral alterations were found. In summary, our data argue that the impact of LRRK2 mutations cannot be simply generalized. Our findings offer mechanistic insights for devising treatment strategies for PD patients.