Characterization of autosomal recessive Parkinson disease-linked parkin mutations.

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder affecting millions of elderly people worldwide. While the majority of PD cases occur in a sporadic manner, a subset of PD cases is attributable to genetic mutations. Among these, mutations in parkin have been identified as one of the predominant causes of familial PD. Although characterized as an autosomal recessive disorder initially, emerging evidence suggests that heterozygous parkin carriers may confer an increased susceptibility to PD. Therefore, it is important to better understand the functional characteristics of the widely presumed “recessive” parkin mutations so as to gain better insights into the disease pathogenesis. In the current study, I’ve shown that whereas several parkin mutations results in the intracellular aggregation of the protein, some mutations accelerate its clearance from the cell by both proteasome and autophagy pathways. Importantly, the formation of mutant parkin inclusions promotes the sequestration and thereby aggregation of soluble wild type parkin. Related to this, parkin aggregation also promotes proteasome dysfunction. Taken together, my results suggest that mutant parkin-mediated aggregation could deplete the pool of functional parkin, and concomitantly compromise proteasome function. Although preliminary, my results provide an attractive mechanistic explanation for the increased disease risk of heterozygous parkin carriers.Bachelor of Science in Biological Science