MGluR5 Modulation Effect on Protein Degradation in Parkinson's Disease

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease that is characterized by motor symptoms and dysregulation of the dopaminergic system. One of the main hallmarks of PD is abnormal alpha-synuclein (α-syn) aggregation that is the main component of Lewy bodies, the formation of which leads to oxidative stress, excitotoxicity and eventual cell death. In out experiment α-syn fibrils and A53T adenovirus will be added to SH-SY5Y cells to mimic PD conditions of protein aggregation and overexpression. In this thesis investigates the possibility of clearing αsyn fibrils from SH-SY5Y cells using an allosteric mGluR5 inhibitor, CTEP. We found that CTEP contributed to significant elimination of α-syn fibrils form SH-SY5Y cells. Assessment of AKT/mTOR pathway has shown that CTEP action is at least in part mTOR dependent. Additionally, we found a significant upregulation of autophagy system components, such as Beclin1, Atg5-Atg12 complex, Atg7, Atg101 and Atg3, and significant downregulation of inhibitory pULK1 in response to CTEP administration. We conclude that CTEP is a useful pharmacological agent that could be used against the abnormal α-syn aggregation.