Retrotransposons as a Source of DNA Damage in Neurodegeneration.

Eugenie Peze-Heidsieck,Rajiv L Joshi,Rania Znaidi,Tom Bonnifet,Julia Fuchs,Camille Ravel-Godreuil,Olivia Massiani-Beaudoin

doi:10.3389/fnagi.2021.786897

Abstract

The etiology of aging-associated neurodegenerative diseases (NDs), such as Parkinson’s disease (PD) and Alzheimer’s disease (AD), still remains elusive and no curative treatment is available. Age is the major risk factor for PD and AD, but the molecular link between aging and neurodegeneration is not fully understood. Aging is defined by several hallmarks, some of which partially overlap with pathways implicated in NDs. Recent evidence suggests that aging-associated epigenetic alterations can lead to the derepression of the LINE-1 (Long Interspersed Element-1) family of transposable elements (TEs) and that this derepression might have important implications in the pathogenesis of NDs. Almost half of the human DNA is composed of repetitive sequences derived from TEs and TE mobility participated in shaping the mammalian genomes during evolution. Although most TEs are mutated and no longer mobile, more than 100 LINE-1 elements have retained their full coding potential in humans and are thus retrotransposition competent. Uncontrolled activation of TEs has now been reported in various models of neurodegeneration and in diseased human brain tissues. We will discuss in this review the potential contribution of LINE-1 elements in inducing DNA damage and genomic instability, which are emerging pathological features in NDs. TEs might represent an important molecular link between aging and neurodegeneration, and a potential target for urgently needed novel therapeutic disease-modifying interventions.

Highlights

Age-associated neurodegenerative diseases (NDs) such as Parkinson’s disease (PD) and Alzheimer’s disease (AD) have become a global burden due to the continued increase in life expectancy with obvious socio-economic implications (Yang et al, 2020)
DNA damage and neuronal cell death in either En1± mice or a toxicological model of PD could be rescued by anti-long interspersed element-1 (LINE-1) strategies such as overexpression of PIWIL1, siRNAs targeting ORF2, or a reverse transcriptase (RT) inhibitor developed in the context of HIV/AIDS treatment, and active against the RT enzyme encoded by ORF2p (Dai et al, 2011; Banuelos-Sanchez et al, 2019)
As we have developed above, the activation of coding LINE-1 and potentially human ERV (HERV) retrotransposons can permit the production of functional DNA cleaving proteins like the LINE-1 encoded EN or the HERV encoded IN, the presence and activity of which endanger the host genome and might contribute to aging and neurodegeneration

Summary

Introduction

Age-associated neurodegenerative diseases (NDs) such as Parkinson’s disease (PD) and Alzheimer’s disease (AD) have become a global burden due to the continued increase in life expectancy with obvious socio-economic implications (Yang et al, 2020). We discuss below the emerging concept that LINE-1 elements might be an additional source of DNA damage and genomic instability and that LINE-1 activation in the brain could be part of the aging process as shown in somatic cells (Gasior et al, 2006; Belancio et al, 2010; De Cecco et al, 2019; Simon et al, 2019) and lead to DNA damage and neurodegeneration (Blaudin de Thé et al, 2018).

Results

Conclusion