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

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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.

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Funding

This work was supported by the Excellent Youth Foundation of Hunan Province (No. 2023JJ10098), National Natural Science Foundation of China (No. 82071437), the Natural Science Foundations of Hunan Province (No. 2021JJ31115), the National Key Research and Development Program of China (No.2021YFC2501200), and the Project Program of National Clinical Research Center for Geriatric Disorders (**angya Hospital) (No.2021KFJJ10).

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Authors and Affiliations

  1. Department of Neurology, **angya Hospital, Central South University, Changsha, China

    Yiting Wu, Tingwei Song & Qian Xu

  2. National Clinical Research Center for Geriatric Disorders, **angya Hospital, Changsha, China

    Qian Xu

  3. Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, China

    Qian Xu

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  1. Yiting Wu
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All authors contributed to the study conception and design. Qian Xu conceived the study. Material preparation, data collection, and analysis were performed by Yiting Wu and Tingwei Song. The first draft of the manuscript was written by Yiting Wu, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Qian Xu.

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Wu, Y., Song, T. & Xu, Q. R-LOOPs on Short Tandem Repeat Expansion Disorders in Neurodegenerative Diseases. Mol Neurobiol 60, 7185–7195 (2023). https://doi.org/10.1007/s12035-023-03531-4

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