Repetitive elements in aging and neurodegeneration

Abstract

Repetitive elements (REs), such as transposable elements (TEs) and satellites, comprise much of the genome. Here, we review how TEs and (peri)centromeric satellite DNA may contribute to aging and neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Alterations in RE expression, retrotransposition, and chromatin microenvironment may shorten lifespan, elicit neurodegeneration, and impair memory and movement. REs may cause these phenotypes via DNA damage, protein sequestration, insertional mutagenesis, and inflammation. We discuss several TE families, including gypsy, HERV-K, and HERV-W, and how TEs interact with various factors, including transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) and the siRNA and piwi-interacting (pi)RNA systems. Studies of TEs in neurodegeneration have focused on Drosophila and, thus, further examination in mammals is needed. We suggest that therapeutic silencing of REs could help mitigate neurodegenerative disorders.

Keywords: aging; neurodegeneration; satellites; transposable elements.

Figure 1.. Abundance of TE subclasses and families across species.

Pie charts display the percentage of the respective genome (human, mouse, or Drosophila melanogaster) constituted by the various subclasses of TEs [1,164,165]. Subclasses that are thought to be inactive in the respective genome are indicated by striped patterns [,–166]. Tables display the percentage of the respective genome (human or mouse) that the various families of TEs constitute [1,164]. These percentages vary between studies, likely due to differences in sequencing methodology and the percentage of heterochromatic sequence analyzed. The data reported here comes from the referenced studies. *The B1 SINEs found in mice and Alu SINEs found in humans are thought to share a common origin, from which they then evolved distinctly in each species [164,167]. Created with BioRender.com.

Figure 2 Key Figure.. Alterations in REs with age and neurodegeneration and their potential causes and effects.

Long-term implications of changes in REs with age and neurodegeneration include neuronal cell death, cognitive and motor dysfunction, shortened lifespan, and disease risk (A). Observed changes in TEs with age and neurodegeneration include increased transcript levels (B), increased successful retrotransposition (C), and decreased repressive marks (D). Possible upstream causes for the increase in transcript levels include a loss of heterochromatin (D) and impairments in post-transcriptional silencing via the siRNA system, piRNA system, or both (E). Increased TE expression correlates with increased levels of DSBs (F). TEs may also exert effects via phase separation (G). Dysfunction of the piRNA system may impair TE silencing at the transcriptional level (H). Reactive oxygen species (ROS) may increase TE expression (I). Observed changes in satellites with age and neurodegeneration so far also include increased transcript levels (B) and decreased repressive marks (D). Like TEs, possible causes for changes in satellite DNA expression involve impairments in heterochromatin (D) and the siRNA system (E). Potential effects of the alterations in TEs and satellites include alterations in the sequence or transcription of the recipient gene (C), increased DSBs (F), phase separation of transcripts (G), impaired mitosis and centromere formation (J), inflammation triggered by cytosolic DNA (K), a loss of heterochromatin from adjacent sequences (L), and an aberrant stress response (M). Consequences of satellite DNA alterations may include shortened lifespan, increased senescence, and cellular death (A). The direct causes of changes to both TE and satellite DNA expression, as well as the mechanisms of their detrimental effects, warrant further examination. Created with BioRender.com.