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. 2018 May 28;9:368. doi: 10.3389/fneur.2018.00368

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Copyright © 2018 André, Ausems, Wansink and Wieringa.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Distinct molecular mechanisms contribute to pathology in myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2). (1) Expanded (CTG)n and (CCTG)n repeats in DMPK and CNBP, or the complementary repeats in the antisense genes (not shown), can cause cellular stress by (1) promoting DNA replication fork stalling and R-loop formation. Expression of repeat-containing sense and antisense RNAs results in (2) sequestration of members of the MBNL protein family, leading to mRNA missplicing, alternative polyadenylation, microRNA (miRNA) deregulation, and transcription deregulation. In addition, (3) CELF1 gets hyperphosphorylated and stabilized, resulting in mRNA missplicing and dysregulation of mRNA stability and translation. (4) Formation of abnormal RNA-protein condensates by repeat RNA and RNA-binding proteins (RBPs) may alter the intracellular distribution fate and biological activity of RBPs. (5) Repeat-associated non-ATG (RAN) translation of the repeats may result in the production of toxic polymeric polypeptides, which perturb cellular proteostasis.