Investigating Convergent Actions of Genes Linked to Familial Parkinson’s Disease

Background: Mutations in LRRK2 are among the most frequent genetic changes identified in Parkinson’s disease (PD), but how LRRK2 contributes to the pathophysiology of PD is not known. Objectives: To investigate how expressing wild-type or G2019S LRRK2 modifies cellular responses to rotenone, a mitochondrial toxin. Methods: We investigated the vulnerability to mitochondrial toxins in Caenorhabditis elegans expressing wild-type or G2019S LRRK2. Results: We observed a powerful role for LRRK2 in mitochondrial biology. Overexpressing LRRK2 strongly protects C. elegans against rotenone toxicity. The G2019S LRRK2 construct also protected LRRK2 against rotenone, but to a lesser degree than wild-type LRRK2. Knockdown of lrk-1 potentiated rotenone toxicity. Conclusions: These data suggest that LRRK1/2 regulate mitochondrial physiology.