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Small molecules which improve pathogenesis of myotonic dystrophy type 1

López-Morató, Marta; Brook, John David; Wojciechowska, Marzena

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Authors

Marta López-Morató

DAVID BROOK david.brook@nottingham.ac.uk
Professor of Human Genetics

Marzena Wojciechowska



Abstract

Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy in adults for which there is currently no treatment. The pathogenesis of this autosomal dominant disorder is associated with the expansion of CTG repeats in the 3′-UTR of the DMPK gene. DMPK transcripts with expanded CUG repeats (CUGexpDMPK) are retained in the nucleus forming multiple discrete foci, and their presence triggers a cascade of toxic events. Thus far, most research emphasis has been on interactions of CUGexpDMPK with the muscleblind-like (MBNL) family of splicing factors. These proteins are sequestered by the expanded CUG repeats of DMPK RNA leading to their functional depletion. As a consequence, abnormalities in many pathways of RNA metabolism, including alternative splicing, are detected in DM1. To date, in vitro and in vivo efforts to develop therapeutic strategies for DM1 have mostly been focused on targeting CUGexpDMPK via reducing their expression and/or preventing interactions with MBNL1. Antisense oligonucleotides targeted to the CUG repeats in the DMPK transcripts are of particular interest due to their potential capacity to discriminate between mutant and normal transcripts. However, a growing number of reports describe alternative strategies using small molecule chemicals acting independently of a direct interaction with CUGexpDMPK. In this review, we summarize current knowledge about these chemicals and we describe the beneficial effects they caused in different DM1 experimental models. We also present potential mechanisms of action of these compounds and pathways they affect which could be considered for future therapeutic interventions in DM1.

Citation

López-Morató, M., Brook, J. D., & Wojciechowska, M. (2018). Small molecules which improve pathogenesis of myotonic dystrophy type 1. Frontiers in Neurology, 9, Article 349. https://doi.org/10.3389/fneur.2018.00349

Journal Article Type Review
Acceptance Date Apr 30, 2018
Online Publication Date May 18, 2018
Publication Date May 18, 2018
Deposit Date Jun 21, 2018
Publicly Available Date Jun 21, 2018
Journal Frontiers in Neurology
Electronic ISSN 1664-2295
Publisher Frontiers Media
Peer Reviewed Peer Reviewed
Volume 9
Article Number 349
DOI https://doi.org/10.3389/fneur.2018.00349
Keywords myotonic dystrophy type 1, myotonic dystrophy type 1 pathogenesis, sequestration of muscleblind-like 1, antisense oligonucleotides, aberrant alternative splicing, small molecule compounds
Public URL https://nottingham-repository.worktribe.com/output/932935
Publisher URL https://www.frontiersin.org/articles/10.3389/fneur.2018.00349/full
Contract Date Jun 21, 2018

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