Jazurek-Ciesiolka, M. | Search bioRxiv

bioRxiv2025

Overview of non-coding RNAs with CAG repeats and the case of mutation-containing circRNA in polyglutamine disease patients

CAG trinucleotide repeats are present in protein-coding and non-coding RNAs (ncRNAs). They are polymorphic in length and can cause neurodegenerative diseases when expanded, e.g., spinocerebellar ataxia type 7 (SCA7) is caused by a mutation in the ATXN7 gene. We focused on RNAs with at least 10 CAG repeats and identified several hundred mRNAs, long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) originating from 49 genomic loci. These loci differ in the rate of length polymorphism in the population, and some of the tracts show an interesting pattern of adjacent CAA triplet, as well as present variable interruption profiles. For ATXN7 locus, we investigated two circRNAs for which we confirmed the expression in the human brain, SCA7 fibroblasts and blood samples. Moreover, we report an intriguing example of circRNA containing a mutant CAG tract, experimentally validated in SCA7 patients.

molecular biology↗

bioRxiv2020

RAN translation of the expanded CAG repeats in the SCA3 disease context

Spinocerebellar ataxia type 3 (SCA3) is a progressive neurodegenerative disorder caused by a CAG repeat expansion in the ATXN3 gene encoding the ataxin-3 protein. Despite extensive research the exact pathogenic mechanisms of SCA3 are still not understood in depth. In the present study, to gain insight into the toxicity induced by the expanded CAG repeats in SCA3, we comprehensively investigated repeat-associated non-ATG (RAN) translation in various cellular models expressing translated or non-canonically translated ATXN3 sequences with an increasing number of CAG repeats. We demonstrate that two SCA3 RAN proteins, polyglutamine (polyQ) and polyalanine (polyA), are found only in the case of CAG repeats of pathogenic length. Despite having distinct cellular localization, RAN polyQ and RAN polyA proteins are very often coexpressed in the same cell, impairing nuclear integrity and inducing apoptosis. We provide for the first time mechanistic insights into SCA3 RAN translation indicating that ATXN3 sequences surrounding the repeat region have an impact on SCA3 RAN translation initiation and efficiency. We revealed that RAN translation of polyQ proteins starts at non-cognate codons upstream of the CAG repeats, whereas RAN polyA proteins are likely translated within repeats. Furthermore, integrated stress response activation enhances SCA3 RAN translation. We suggest that RAN translation in SCA3 is a common event substantially contributing to SCA3 pathogenesis and that the ATXN3 sequence context plays an important role in triggering this unconventional translation.

molecular biology↗