Exogenous α-Synuclein Induces Oxidative Damage to Dopaminergic Neurons Through p-NMDAR2B/Nur77.

Abstract

Alpha-synuclein (α-syn) is a major pathological marker of Parkinson's disease (PD), and its abnormal expression and aggregation lead to dopaminergic neuron degeneration, in which oxidative stress plays an important role. However, the exact molecular mechanism by which α-syn causes PD remains unclear. In this study, exogenous α-syn, also known as α-syn preformed fibrils (α-syn PFFs), was used to construct in vivo and in vitro models of PD. Behavioral, Western blotting, biochemical, immunofluorescence, flow cytometry, electron microscopy, etc. were used to investigate the pathological mechanism of PD induced by α-syn. We found that 6 months after striatum injection of α-syn PFFs, mice exhibited motor deficits. Meanwhile, the protein expression of pS129-α-syn (p-α-syn) and α-syn oligomer significantly increased, while the expression of TH significantly decreased, and the oxidative stress in the substantia nigra was aggravated. In addition, we found an increase in the protein expression of NMDAR2B and p-Tyr1472-NMDAR2B (p-NMDAR2B) and a decrease in the protein expression of Nur77. However, in α-syn PFFs-induced SH-SY5Y cells, we found that inhibiting p-NMDAR2B increased the protein expression of Nur77, while overexpression of Nur77 did not affect the expression of p-NMDAR2B. Inhibition of p-NMDAR2B and overexpression of Nur77 reversed α-syn PFF-induced oxidative stress, thus reducing mitochondrial damage and cytotoxicity. Therefore, we speculate that α-syn PFF-induced oxidative stress in dopaminergic neurons may be mediated by p-NMDAR2B/Nur77. Our study provides novel insights into the pathology mechanism underlying α-syn-induced PD.