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 wildtype 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 wildtype LRRK2. Knockdown of Irk-1 potentiated rotenone toxicity. Conclusions: These data suggest that LRRK1/2 regulate mitochondrial physiology. Copyright (c) 2008 S. Karger AG, Basel.