SIRT1 Deacetylates TET2 and Promotes Its Ubiquitination Degradation to Achieve Neuroprotection Against Parkinson's Disease.

Xuan Li,Yun-Cheng Wu,Huiyong Yin,Si-Jia Peng,Te Liu,Ting-Ting Wu,Ya Feng

doi:10.3389/fneur.2021.652882

Abstract

The epigenetic modifications, such as DNA methylation and histone acetylation, play a critical role in the pathogenesis of Parkinson's disease (PD). However, the relationship between DNA methylation and histone acetylation in PD is not fully understood. Previous studies have shown that patients with PD exhibit an epigenetic and transcriptional upregulation of Ten-Eleven Translocation 2 (TET2), a member of the DNA hydroxylases family. Silence information regulator 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase, also plays a critical role in PD development and might be a potential target for PD therapy. Our previous data indicated that demethylation in the Cyclin-dependent kinase inhibitor 2A (CDKN2A) promoter by the TET2 directly activated its expression, then promoted the cell cycle arrest and cell death induced by 1-methyl-4-phenyl-pyridinium ion (MPP+). In this study, we found that the enzyme activity of SIRT1 is negatively correlated with the protein level of TET2. In addition, the deacetylation of TET2 induced by SIRT1 promotes TET2 degradation via the ubiquitin–proteasome pathway. Furthermore, the activation of endogenous SIRT1 by resveratrol (RV) leads to CDKN2A DNA hypermethylation due to the decreased TET2 protein levels, which relieves the inhibitory effect on CDK4 and upregulation of pRb, allowing cell proliferation and growth. Similar effects are observed for the inhibition of endogenous TET2 enzyme activity with TET2 inhibitor. Together, we discover a new mechanism by which the SIRT1-TET2-CDKN2A pathway is involved in the pathogenesis of PD, which may provide a potential target for PD treatment.

Highlights

Parkinson’s disease (PD) is the second most common neurodegenerative disease, affecting about 1.0% of the population over 60 years of age and 3.0% of the population over 80 years of age [1]
The ratio of B-cell lymphoma 2 protein (Bcl-2)/Bcl-2-associated X protein (Bax) protein regulates the sensitivity of cells to apoptosis: the higher this ratio is, the less sensitive the cells are to apoptosis
Our results showed that pre-treatment with RV reversed the neurotoxicity of MPP+ by promoting Bcl-2/Bax ratio, indicating that RV can reduce SHSY5Y cells damage caused by neurotoxin through inhibiting apoptosis (Figures 1F,G)

Summary

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disease, affecting about 1.0% of the population over 60 years of age and 3.0% of the population over 80 years of age [1]. The pathogenesis of PD includes mitochondrial dysfunction, oxidative stress, inflammation, genetic factors, epigenetic modifications, etc. The causative factors of neurodegenerative process affecting the etiopathogenesis of PD remain unknown [3]. DNA modifications, DNA methylation, show the most promise for epigenetic biomarker development in neurodegenerative diseases recently. Given the known influence of α-synuclein expression levels in PD, initial DNA methylation studies focused on the SNCA gene. It has been reported that the methylation of human SNCA intron 1 decreased gene expression while the inhibition of DNA methylation activated its expression in the brains of PD patients [6].

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