Marta López-Morató
Small molecules which improve pathogenesis of myotonic dystrophy type 1
López-Morató, Marta; Brook, John David; Wojciechowska, Marzena
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 |
Files
fneur-09-00349.pdf
(1.3 Mb)
PDF
Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0
You might also like
Downloadable Citations
About Repository@Nottingham
Administrator e-mail: discovery-access-systems@nottingham.ac.uk
This application uses the following open-source libraries:
SheetJS Community Edition
Apache License Version 2.0 (http://www.apache.org/licenses/)
PDF.js
Apache License Version 2.0 (http://www.apache.org/licenses/)
Font Awesome
SIL OFL 1.1 (http://scripts.sil.org/OFL)
MIT License (http://opensource.org/licenses/mit-license.html)
CC BY 3.0 ( http://creativecommons.org/licenses/by/3.0/)
Powered by Worktribe © 2024
Advanced Search