Senescence and impaired DNA damage responses in alpha-synucleinopathy models

Seung-Jae Lee,Darlene Ortiz,He-Jin Lee,Tae-Kyung Kim,Ye-Seul Yoon,Myoung Jun Kim,Woo Jung Ahn,Jueng Soo You,Keun Hong Son,Diadem Ricarte

doi:10.1038/s12276-022-00727-x

Abstract

α-Synuclein is a crucial element in the pathogenesis of Parkinson’s disease (PD) and related neurological diseases. Although numerous studies have presented potential mechanisms underlying its pathogenesis, the understanding of α-synuclein-mediated neurodegeneration remains far from complete. Here, we show that overexpression of α-synuclein leads to impaired DNA repair and cellular senescence. Transcriptome analysis showed that α-synuclein overexpression led to cellular senescence with activation of the p53 pathway and DNA damage responses (DDRs). Chromatin immunoprecipitation analyses using p53 and γH2AX, chromosomal markers of DNA damage, revealed that these proteins bind to promoters and regulate the expression of DDR and cellular senescence genes. Cellular marker analyses confirmed cellular senescence and the accumulation of DNA double-strand breaks. The non-homologous end joining (NHEJ) DNA repair pathway was activated in α-synuclein-overexpressing cells. However, the expression of MRE11, a key component of the DSB repair system, was reduced, suggesting that the repair pathway induction was incomplete. Neuropathological examination of α-synuclein transgenic mice showed increased levels of phospho-α-synuclein and DNA double-strand breaks, as well as markers of cellular senescence, at an early, presymptomatic stage. These results suggest that the accumulation of DNA double-strand breaks (DSBs) and cellular senescence are intermediaries of α-synuclein-induced pathogenesis in PD.

Highlights

INTRODUCTION αSynuclein is an abundant neuronal protein with an intrinsically disordered structure[1]
Our results showed that α-synuclein in human neuronal cells increased double-strand breaks (DSBs) with impaired DNA repair. α-Synuclein-induced impairment of DSB repair leads to increased levels of senescence markers
We examined the levels of another DSB marker, the phosphorylated form of ataxia telangiectasia mutated

Summary

Introduction

Synuclein is an abundant neuronal protein with an intrinsically disordered structure[1]. This protein is abnormally folded and aggregated in several neurodegenerative diseases, referred to as α-synucleinopathies, such as dementia with Lewy bodies, multiple system atrophy, and Parkinson’s disease (PD)[2]. These diseases affect millions of people worldwide, with the distinct characteristics of intracytoplasmic protein aggregates and a gradual increase in neuronal death in particular areas of the brain. Brain autopsy studies of aged people without a PD diagnosis have reported brain and spinal cord atrophy; decreases in the volume of gray matter; accumulation of pathological protein aggregates, such as amyloid plaques, neurofibrillary tangles, and Lewy bodies; and inclusions of TAR DNA-binding protein 43 and senescent cells[4,5]

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