SIRT1 ameliorates oxidative stress induced neural cell death and is down-regulated in Parkinson\u2019s disease

Preeti Singh,Peter S Hanson,Christopher M Morris

doi:10.1186/s12868-017-0364-1

Preeti Singh, Peter S Hanson + Show 1 more

Open Access

https://doi.org/10.1186/s12868-017-0364-1

Copy DOI

Abstract

Background Sirtuins (SIRTs) are NAD+ dependent lysine deacetylases which are conserved from bacteria to humans and have been associated with longevity and lifespan extension. SIRT1, the best studied mammalian SIRT is involved in many physiological and pathological processes and changes in SIRT1 have been implicated in neurodegenerative disorders, with SIRT1 having a suggested protective role in Parkinson’s disease. In this study, we determined the effect of SIRT1 on cell survival and α-synuclein aggregate formation in SH-SY5Y cells following oxidative stress.ResultsOver-expression of SIRT1 protected SH-SY5Y cells from toxin induced cell death and the protection conferred by SIRT1 was partially independent of its deacetylase activity, which was associated with the repression of NF-кB and cPARP expression. SIRT1 reduced the formation of α-synuclein aggregates but showed minimal co-localisation with α-synuclein. In post-mortem brain tissue obtained from patients with Parkinson’s disease, Parkinson’s disease with dementia, dementia with Lewy bodies and Alzheimer’s disease, the activity of SIRT1 was observed to be down-regulated.ConclusionsThese findings suggests a negative effect of oxidative stress in neurodegenerative disorders and possibly explain the reduced activity of SIRT1 in neurodegenerative disorders. Our study shows that SIRT1 is a pro-survival protein that is downregulated under cellular stress.

Highlights

Sirtuins (SIRTs) are NAD+ dependent lysine deacetylases which are conserved from bacteria to humans and have been associated with longevity and lifespan extension
Given the possible protective role of sirtuin 1 (SIRT1) in Parkinson’s disease (PD), we evaluated the role of SIRT1 and its enzymatic activity in oxidative stress mediated cell death and characterised the involvement of SIRT1 in PD
SIRT1 overexpression and toxin treatment in SH‐SY5Y cells Wild type SIRT1 (Flag-SIRT1 was a generous gift from Michael Greenberg; Addgene; Plasmid number 1791) and catalytically inactive SIRT1H363Y (Flag-SIRT1 H363Y; Addgene; Plasmid number 1792 from Michael Greenberg) plasmids [14] were obtained from Addgene and sub-cloned in pLenti CMV blast and empty pLenti CMV blast wild type served as a control [15]

Summary

Introduction

Sirtuins (SIRTs) are NAD+ dependent lysine deacetylases which are conserved from bacteria to humans and have been associated with longevity and lifespan extension. SIRT1, the best studied mammalian SIRT is involved in many physiological and pathological processes and changes in SIRT1 have been implicated in neurodegenerative disorders, with SIRT1 having a suggested protective role in Parkinson’s disease. SIRT1 is a N AD+ dependent class III histone deacetylase that shares homology with yeast silent information regulator, SIR2. SIRT1 targets histones and non-histones proteins that are involved in the regulation of several physiological processes including mitochondrial biogenesis, antioxidant defence mechanisms, DNA repair, apoptosis and genomic stability [2]. SIR2 promotes lifespan extension in yeast [3] and brain specific overexpression of its Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease (AD) and the most common neurodegenerative movement disorder [7, 8].

Methods

Results

Conclusion