Retrotransposons as a Source of DNA Damage in Neurodegeneration

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.

The Role of Transposable Elements of the Human Genome in Neuronal Function and Pathology

“…To date, multiple authors have provided evidence that TE activity may be involved in pathogenesis of Alzheimer’s disease, autism, schizophrenia, Rett syndrome, ataxia-telangiectasia, amyotrophic lateral sclerosis, macular degeneration and some other neuropathologies [ 39 , 56 , 112 , 113 , 350 , 466 ]. Physiological conditions such as stress and aging are not formally considered disorders, but since they are associated with some detrimental effects as well as with TE derepression [ 384 , 467 , 468 , 469 ], we discuss these conditions as well.…”

“…Aging is a result of gradual accumulation of damage in cells and tissues [ 469 ]. A phylogenetically conserved feature of aging is induction of stress response pathways that was confirmed in all systems studied, including whole organism analysis of invertebrates and analysis of the brain of different mammalian species [ 480 ].…”

“…Moreover, even normal aging in healthy people includes decrements in learning and memory, attention, decision-making speed, sensory perception and motor coordination, and even reduction in brain size [ 476 ]. Many pathological features of neurodegeneration are aggravated hallmarks of normal brain aging (including genomic instability and epigenetic alterations), suggesting that neurodegeneration may be actually seen as accelerated aging [ 468 , 469 ]. One of the most important mechanisms in neuronal aging and age-associated cognitive impairment is oxidative damage [ 482 ].…”

Immune-mediated neurodegenerative trait provoked by multimodal derepression of long-interspersed nuclear element-1

“…For example, endogenous retroelements are getting considerable attention as a potential class of alternative tumor-specific antigens ( Smith et al., 2019 ). Interestingly, dysregulated increase of endogenous retroelements has also been associated with NDs ( Peze-Heidsieck et al., 2021 ; Ravel-Godreuil et al., 2021 ): high levels of expression and reactivation of retrotransposable element, LINE-1 (Long interspersed nuclear element 1, L1), in postmortem brain samples of ALS and FTD ALS in TDP-43 (TAR DNA-binding protein of 43 kDa)-dependent manner ( Liu et al., 2019 ; Tam et al., 2019 ). Thus, aberrant expression of endogenous retroelement under chronic inflammation could provide the currently unknown antigen(s) that may prime Th cell in the CNS.…”

“…Meanwhile, dysregulated L1 insertion potentially compromises developing and mature neurons and so may cause neurodevelopmental diseases and neurodegenerative diseases ( Nicole et al., 2017 ). Interestingly, L1 activation has been frequently highlighted as a comorbidity in NDs ( Peze-Heidsieck et al., 2021 ; Ravel-Godreuil et al., 2021 ). However, comprehensive analysis of the mode of L1 activation and its relevance to neuronal cell death remains to be investigated.…”