Analysis of Myotonic Dystrophy and the Role of Transcription and Translation in its Pathology
Myotonic Dystrophy is, according to the literature, “the most common form of muscular dystrophy” 1,2. It can be characterised in a number of ways, with varying symptoms including myotonia, cataracts, cardiac conduction issues and can even cause infertility in men 1. Myotonic dystrophy falls into two categories: type 1 and type 2 1. This essay will focus on type 1, a more common type that is characterised by a mutation in myotonic dystrophy protein kinase (DMPK) 3,4.
The DMPK mutation is caused by CUG/CTG repeats in RNA, forming CUGn areas in the 3’ untranslated regions 4–6. This CUGn RNA can induce stress granule formation, following inactivation of elF2a, via increases of RNA-dependent protein kinase (PKR) 5. This is demonstrated to cause mRNA code trapping, by stress granules, of the DNA repair factor MRG15; this reduces MRG15 levels in type 1 myotonic dystrophy (DM1) cells 5. MRG15 is a transcription factor that is thought to be involved in chromatin remodelling due to its association with histone acetyltransferases 7. Knocking out this factor has been demonstrated to cause cell proliferation defects and reduced cell growth 7, indicating the potential for similar downstream effects in DM1 cells leading to muscle degeneration that is characteristic of myotonic dystrophy 1. CUG/CTG repeats also cause GSK3β increases, which leads to the reduction in phosphorylation of Ser302 moieties in CUG RNA-binding proteins (CUGBP1) downstream 6. Build up of these CUGBP1 isoforms causes repression of translation 6.
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These effects cause a number of morphological changes in the induced pluripotent stem (iPS) cells of myotonic dystrophy patients 8. The continuous creation of RNA foci causes a build up in RNA aggregates 9. These aggregates can adopt uncommon structures and sequester various RNA binding proteins, leading to pressure build up in the nucleus and eventual cell toxicity 9,10. The iPS cells are also at a reduced level of potency due to their mutations, causing DM1 iPS-derived neural stem cells (NSCs) to display aberrant splicing, leading to degeneration 8.
Myotonic dystrophy is hereditary, with the offspring of each patient having earlier onset and increased severity through the generations in a process called ‘anticipation’ 11. This happens through the maternal line, with the CTG/CUG repeats increasing drastically in each generation, for example a mother with 230 CTG/CUG repeats may have offspring that have between 630 and 730 repeats, increasing severity and lowering age of onset 11. The most prominent symptom of myotonic dystrophy is weakness of distal muscles, due to not only degeneration but also to axonal peripheral neuropathy 11,12. Myotonic dystrophy patients show significant reduction in compound muscle action potentials when compared to a control population, possibly caused by a prolonged recovery period after firing 12. Another prominent symptom of the disease is myotonia, characterised by delayed relaxation of muscle groups following voluntary contraction 11,13,14. This commonly characterises in the facial muscles as a speech disability known as flaccid dysarthria 13,15. This can cause speech to become impaired in several different ways and is often the first sign of onset of myotonic dystrophy 13,15. Central nervous system effects differ in severity depending on the age of onset, earlier onset of the disease can cause significant setbacks to cognitive milestones 11,16, whereas adults have less of a reduction in cognitive function 11,16,17. In fact, in tests of cognitive function, myotonic dystrophy patients show little reduction compared to controls but do show reduction in prefrontal functioning 17 and “aging-related decline in frontal and temporal cognitive function” 16.
Myotonic dystrophy is generally not treatable in the traditional sense, but can be managed through a number of different avenues 2,11. Management is usually done through replacement of various molecules that link to muscle strength, development and density 11,18–20. The first of which is dehydroepiandrosterone (DHEA), an androgen and steroid linked to muscular development 18,19. DHEA has been shown to repress myotonia and decrease isometric twitch tension by up to 70% in mice with decreased Cl channel development, a standard animal model of myotonia 18. This study, although applicable to one aspect of myotonia development, lacks in a holistic view as there is little focus on transcriptional efficiency in these mutant mice. It also does not show any evidence that this method may reduce muscle degeneration, a key clinical manifestation of myotonic dystrophy. Human studies, such as the one by Sugino et al. demonstrate a more robust argument for DHEA treatment, although having a limited sample size 19. A more novel treatment pathway is that of SMAUG1/SMAD4A (smaug) 21. Smaug is a translational switch that acts on RNA 22, it has been shown to restore the action of CUGBP1 to correct the translation of MRG15, making it a modulator of CUG-linked cell toxicity and reducing muscle wasting and weakness 21. These findings are specifically applicable to myoblasts and, although there were strong links to the downstream affects of CUGBP1 to reduce RNA foci build up, there are also indications that smaug can regulate alternative splicing 21 which may account for the therapeutic effects seen through normalised protein isoforms.
3. Krahe R, Ashizawa T, Abbruzzese C, Roeder E, Carango P, Giacanelli M, et al. Effect of myotonic dystrophy trinucleotide repeat expansion on DMPK transcription and processing. Genomics. 1995 Jul 1;28(1):1–14.
5. Huichalaf C, Sakai K, Jin B, Jones K, Wang G-L, Schoser B, et al. Expansion of CUG RNA repeats causes stress and inhibition of translation in myotonic dystrophy 1 (DM1) cells. FASEB J. 2010 Oct;24(10):3706–19.
8. Gao Y, Guo X, Santostefano K, Wang Y, Reid T, Zeng D, et al. Genome Therapy of Myotonic Dystrophy Type 1 iPS Cells for Development of Autologous Stem Cell Therapy. Mol Ther. 2016 Aug;24(8):1378–87.
9. Walsh MJ, Cooper-Knock J, Dodd JE, Stopford MJ, Mihaylov SR, Kirby J, et al. Invited review: decoding the pathophysiological mechanisms that underlie RNA dysregulation in neurodegenerative disorders: a review of the current state of the art. Neuropathol Appl Neurobiol. 2015 Feb;41(2):109–34.
13. de Swart BJM, van Engelen BGM, van de Kerkhof JPBM, Maassen BAM. Myotonia and flaccid dysarthria in patients with adult onset myotonic dystrophy. J Neurol Neurosurg Psychiatry. 2004 Oct;75(10):1480–2.
14. Logigian EL, Blood CL, Dilek N, Martens WB, Moxley RT IV, Wiegner AW, et al. Quantitative analysis of the “warm-up” phenomenon in myotonic dystrophy type 1. Muscle & Nerve: Official Journal of the American Association of Electrodiagnostic Medicine. 2005;32(1):35–42.
17. Gaul C, Schmidt T, Windisch G, Wieser T, Müller T, Vielhaber S, et al. Subtle cognitive dysfunction in adult onset myotonic dystrophy type 1 (DM1) and type 2 (DM2). Neurology. 2006 Jul 25;67(2):350–2.
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