Research Paper Volume 14, Issue 20 pp 8292—8301
α-Synuclein upregulates bim-mediated apoptosis by negatively regulating endogenous GCN5
- 1 Department of Applied Life Science, Graduate School, BK21 Program, Konkuk University, Chungju 27478, Korea
- 2 Department of Biotechnology, College of Biomedical and Health Science, Research Institute of Inflammatory Disease (RID), Konkuk University, Chungju 27478, Korea
Received: August 25, 2022 Accepted: October 14, 2022 Published: October 27, 2022
https://doi.org/10.18632/aging.204353How to Cite
Copyright: © 2022 Azam et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
α-synuclein (αS) is a β-sheet intracellular protein that has been implicated as a major pathological hallmark of Parkinson’s disease (PD). Several studies have shown that overexpression of αS causes dopaminergic cell loss; however, the role of αS in apoptosis remains not fully known. Therefore, this study aims to address the mechanisms of the αS overexpression model in apoptosis and to its correlation with PD pathogenesis. Here, we used a human αS (hαS) plasmid to characterize the role of ectopic αS in neuronal apoptosis in sporadic PD in vitro. We found that overexpression of αS transcriptionally upregulated Bim-mediated apoptosis in neuronal SH-SY5Y cells. Interestingly, αS overexpression inhibited general control non-depressible 5 (GCN5), a histone acetyltransferase (HAT), and promoted transcriptional upregulation of Bim. Consequently, co-overexpression of GCN5 in the αS overexpressed model showed a reversal of αS toxicity in neuronal cells. These in vitro findings support the hypothesis of αS-mediated histone deacetylation and dopaminergic neuronal loss in PD. Moreover, our study indicates that therapeutic activation/homeostasis of GCN5 may benefit PD and other α-synucleinopathies.