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Funded Studies

Intracellular Trafficking Dysfunction Caused by Alpha-synuclein Aggregation

A growing body of evidence suggests that aggregation of a neuronal protein named a-synuclein might be the fundamental cause of many neurodegenerative diseases, such as Parkinson's disease (PD), dementia with Lewy bodies (LBs), and LB variant of Alzheimer's disease. However, the link between a-synuclein aggregation and cellular dysfunction/death has not been clearly addressed, nor are the molecular mechanisms underlying the toxicity known. The current study aims to identify specific cellular impairment caused by a-synuclein aggregation, and to find ways to prevent or reverse the deleterious effects of a-synuclein aggregates. Function and survival of neurons depend on the efficient transport of proteins and chemicals through long processes called axons and dendrites, which connects one neuron to another to form a neural circuit. The microtubules and its motor proteins mediate this long-range transport. In the current study, we will test the hypothesis that extensive a-synuclein aggregation in neurons may place an excessive burden on the microtubule transport system, causing it to malfunction. We will also test whether inhibiting aggregation may protect the cells from this impairment. To this end, we will investigate the effects of a-synuclein overproduction and consequent aggregation on the rate of intracellular trafficking by following the trafficking of transferrin receptor, a well-characterized cargo protein of the microtubule transport system. Secondly, the role of a-synuclein aggregation in cellular dysfunction will be further validated by demonstrating the correlation between the aggregation and trafficking impairment using (i) PD-linked mutant variants, and (ii) the co-expression of potential anti-aggregation proteins such as b-synuclein and parkin. This study should greatly enhance our understanding of the pathogenic mechanisms of a-synucleinopathies, and could eventually lead to effective therapeutic strategies to slow or halt the progression of PD and other LB diseases.


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