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Review
. 2023 Dec;60(12):7185-7195.
doi: 10.1007/s12035-023-03531-4. Epub 2023 Aug 4.

R-LOOPs on Short Tandem Repeat Expansion Disorders in Neurodegenerative Diseases

Yiting Wu  1 , Tingwei Song  1 , Qian Xu  2   3   4
Affiliations
Review

R-LOOPs on Short Tandem Repeat Expansion Disorders in Neurodegenerative Diseases

Yiting Wu et al. Mol Neurobiol. 2023 Dec.

Abstract

Expansions of short tandem repeats (STRs) have been found to be present in more than 50 diseases and have a close connection with neurodegenerative diseases. Transcriptional silencing and R-LOOP formation, RNA-mediated sequestration of RNA-binding proteins (RBPs), gain-of-function (GOF) proteins containing expanded repeats, and repeat-associated non-AUG (RAN) translation of toxic repeat peptides are some potential molecular mechanisms underlying STR expansion disorders. R-LOOP, a byproduct of transcription, is a three-stranded nucleic acid structure with abnormal accumulation that participates in the pathogenesis of STR expansion disorders by inducing DNA damage and genome instability. R-LOOPs can engender a series of DNA damage, such as DNA double-strand breaks (DSBs), single-strand breaks (SSBs), DNA recombination, or mutations in the DNA replication, transcription, or repair processes. In this review, we provide an in-depth discussion of recent advancements in R-LOOP and systematically elaborate on its genetic destabilizing effects in several neurodegenerative diseases. These molecular mechanisms will provide novel targets for drug design and therapeutic upgrading of these devastating diseases.

Keywords: DNA damage; Neurodegenerative diseases; R-LOOPs; Short tandem repeat expansion disorders.

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