The Juvenile Parkinson's Disease Mutation C212Y Impairs Mitochondrial Homeostasis in a Caenorhabditis elegans Model

Inherited Parkinson's disease (PD) often involves missense mutations in the PRKN2 gene, encoding for Parkin protein. The PDR‐1 protein is the C. elegans ortholog of human Parkin . Using a CRISPR/Cas9 genome editing approach, we generated the PDR‐1 C169Y point mutation on a conserved cysteine residue in the RING0 domain. This mutation in human Parkin , C212Y, has been identified in autosomal recessive juvenile Parkinsonism patients. The PDR‐1 C169Y homozygous mutant animals exhibited a shorter lifespan and decreased thrashing rate compared with wild‐type or heterozygous animals. Unique mitochondrial phenotypes were observed, including an increased mitochondrial area and mitochondrial membrane potential. However, these phenotypes did not activate the mitochondrial unfolded protein response. Pan‐neuronal analysis revealed decreased mitophagy. Dopaminergic neurodegeneration in aged animals was not enhanced when compared to WT. Our findings suggest that analysis of the recessive missense point mutations found in early‐onset PD using the C. elegans model system has the potential to advance our understanding of the molecular mechanisms that lead to neurodegeneration.