Pathogenic LRRK2 R1441C mutation is associated with striatal alterations

LRRK2 mutations are associated with both familial and sporadic forms of Parkinson’s disease (PD). Convergent e vidence 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 impaired striatal-dependent motor learning in the R1441C knock-in mice. In contrast, no detectable alterations were observed in the G2019S knock-in mice. In summary, our data argue that the impact of individual LRRK2 mutations cannot be simply generalized. Our findings have far-reaching implications for devising treatment strategies for PD patients.