Understanding the Effect of N-Terminal Acetylation on alpha-Synuclein Toxicity

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Parkinson's Disease (PD) is a debilitating neurodegenerative movement disorder, whose clinical markers include the formation of alpha-Synuclein (alpha-Syn) rich aggregates in the substantia nigra . Despite the identification of alpha-Syn, a 14 kDa protein, as a target of interest in the treatment of PD, much remains unknown about this protein. Factors behind its aggregation and toxicity are unclear, however studies have indicated that posttranslational modifications play an important role. N-terminal acetylation has been seen as a potential factor in the disease state, yet this modification remains largely unstudied. This project is designed to clarify the role of N- terminal acetylation and the effects of this modification on alpha-Syn. The stability and toxicity of the modified and unmodified proteins will be determined through in vivo assays in yeast studying the aggregation and subcellular localization of alpha-Syn. Structural studies utilizing circular dichroism and NMR spectroscopy will examine any structural changes resulting from the posttranslational modifications. The effect of these posttranslational modifications on the PD-associated mutants, A30P, E46K, and A53T, will also be studied. This project will provide insight into the cause of alpha-Syn toxicity, aiding structure-based drug design efforts. PUBLIC HEALTH RELEVANCE: Parkinson's disease, a debilitating movement disorder, is the second most prevalent neurodegenerative disease after Alzheimer's disease(1). Aggregation of a 14 kDa protein, alpha-Synuclein, has been identified as a histopathological hallmark of the disease, however many questions remain that hinder drug design efforts. This project is designed to further probe the structure, stability and toxicity of alpha-Synuclein, improving understanding of this important drug target.