Study of the Metabolism and Aggregation of Alpha-synuclein in Parkin-depleted Neuronal Cells

While only a small fraction of Parkinson's disease (PD) cases are genetic, they possess most of the common clinical and pathological features of PD, which ordinarily has no traceable cause. As this suggests that the underlying biochemistry is similar despite the difference in the cause of the disease, the genetic form of PD may serve as an ideal model for the study of PD. Recently, a form of early-onset PD was linked to mutations in a gene named parkin. Parkin serves to break down abnormal cellular proteins via the ubiquitin-proteasome system. It has been hypothesized that parkin is important in regulating the metabolism and aggregation of a-synuclein (a-syn), a protein that is thought to be the critical protein in the pathogenesis of PD. If this hypothesis is to be tested, it is crucial that the experimental system allows for the examination of what happens when normal parkin function is eliminated. In the proposed study, we will suppress the natural expression of parkin in neurons using a technique called RNA interference (RNAi), and investigate its effects on a-syn metabolism and aggregation.