Proteomic differences and protein acetylation by sirtuins in response to cell aging

Liting Deng, Mehdi Mirzaei, Paul Haynes*

*Corresponding author for this work

Research output: Contribution to conferencePoster

Abstract

Introduction: Ageing is the main risk factor for many prevalent diseases (cancer, cardiovascular disease and neurodegeneration), and has become one of the most significant societal issues in 21st century. There are as yet no efficient therapies to slow ageing processes and lengthen life expectancy. Sirtuins, a family of well-known NAD+-dependent deacetylase proteins, are reported to have anti-ageing functions and show beneficial effects against age-related diseases, including Alzheimer’s disease (AD) in animal models. They are involved in chemical reversal of acetyl lysine modifications of cellular proteins. Deacetylation catalyzed by sirtuins is implicated in regulating diverse biological processes involved in ageing and related neurodegenerative diseases.

Methods: In our studies, multiplexed Tandem Mass Tag based proteomics analysis was separately applied to 1. mice cells treated with Aβ toxic peptides (5µM/6hours, 5µM/24hours, 25µM/6hours, 25µM/24hours), and 2. different mice brain tissues (hippocampus, cerebellum, frontal and parietal cortex) from both young and old APP/PS1 transgenic model mice, and their matched controls. Comprehensive functional pathway and protein network interaction analysis were performed using Ingenuity, STRING, Panther and Cytoscape plugin analysis tools.

Preliminary Data: Decreased expression of sirtuin signalling pathway was observed when mice cells were exposed to Aβ (5um and 25 µM) in the initial stage (6 hours). This pathway was reported to protect the cells against Aβ toxic effects. Sirt2 and sirt5 were identified in specific brain tissues (hippocampus, frontal and parietal cortex) from both young and old mice brain. Increased abundance of sirt5 was only observed in frontal cortex while sirt2 expression differed between tissues. Sirt2 was lower in abundance in hippocampus but greater in abundance in frontal and parietal cortex with AD, which may indicate the different progress of neurodegeneration in specific brain areas with AD, and the functional regulation of sirt2. Sirtuin proteins are stress response proteins, and sirt2 and sirt5 were reported to protect neurogenesis and inhibit the inflammation by activating deacetylase activity. The increased expression of sirtuin proteins in frontal and parietal cortex, especially sirt2, may explain their important roles in neuroprotection, as sirt2 was reported to protect neural cells from oxidative stress and elevated in neurodegeneration. Decreased sirt2 in hippocampus correlates with previous findings indicating that hippocampus is the area in the brain most affected by AD. Further research will apply proteomics to yeast sirtuin mutants to better characterize functions of sirtuins and identify the modulated proteins involved in ageing process and relevant diseases. This will include identifying which proteins in cells show increased and decreased extent of acetylation as the cells age, and how this phenotype is altered by deletion of specific sirtuins.

Novel Aspect :Protein sirtuins, especially sirt2, may play an important role during cell aging and neurodegenerative disorder processing.

Original languageEnglish
Publication statusPublished - 2019
EventASMS Conference on Mass Spectrometry and Allied Topics (67th : 2019) - Atalnta, United States
Duration: 2 Jun 20196 Jun 2019

Conference

ConferenceASMS Conference on Mass Spectrometry and Allied Topics (67th : 2019)
CountryUnited States
CityAtalnta
Period2/06/196/06/19

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