Mitochondrial Dysfunction and Protein Aggregation in the Cybrid Cell Model of Parkinson's Disease 1139 views

Parkinson’s disease (PD) is the most common motor neurodegenerative disease that affects approximately 1 million patients in the United States. The cause of PD in a majority of patients is currently unknown. PD neuropathology is characterized by a loss of dopaminergic (DA) neurons and the formation of intracellular protein aggregates, called Lewy bodies (LB). The presence of these protein aggregates suggests that a decline in protein degradation may play an important role in PD pathogenesis. In addition, mitochondrial dysfunction has also been reported in PD patient brain and periphery. In an effort to better understand PD pathogenesis, we investigated the relationship between mitochondrial function and protein aggregation in the cybrid model of PD, which forms intracellular aggregates similar to LB, called cybrid LB (CLB). The role of LB formation in PD is controversial. In an effort to determine if CLB are detrimental or cytoprotective to cybrid cells, we selected cells containing CLB and generated sub-cloned cell lines. We anticipated that there would be a consistent change across the sub-cloned lines; however, instead we found that the heterogeneity between the different original PD cybrid lines produced variable mitochondrial phenotypes in the sub-cloned lines. This suggests that protein aggregation does not have a consistent relationship with mitochondrial function. Next, we expressed a yeast electron transport chain gene, Ndi1, to bypass the dysfunctional complex I in a PD cybrid cell line. We were able to significantly improve mitochondrial function by expressing Ndi1; however, we did not prevent CLB formation. The findings from these first two studies led us to investigate if autophagy was involved in both mitochondrial function and CLB formation. By inhibiting autophagy, we observed a significant decline in mitochondrial function, suggesting autophagy plays an important role in maintenance of mitochondrial function. We also found that autophagic proteins are incorporated into the CLB, implicating a role for autophagy in CLB formation and growth. These studies indicate that there is an essential role for autophagy in both the maintenance of mitochondrial function, as well as CLB formation. These findings have uniquely advanced our understanding o

PHD (Doctor of Philosophy)

Parkinson's disease; mitochondria; autophagy

English

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2013-09-05