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The Role of Mutant RNA in the Pathogenesis of Huntington’s Disease and Other Polyglutamine Diseases

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Abstract—

Polyglutamine diseases are rare, inherited neurodegenerative pathologies that arise as a result of expansion of trinucleotide CAG repeats in the coding segment of certain genes. This expansion leads to the appearance of mRNA with abnormally long repetitive CAG triplets (mCAG-RNA) and proteins with polyglutamine (PolyQ) tracts in the cells, which is why these pathologies are commonly termed polyglutamine diseases, or PolyQ diseases. To date, nine PolyQ diseases have been described: Huntington’s disease, dentatorubral pallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA), and six different types of spinocerebellar ataxia (SCA 1, 2, 3, 6, 7, and 17). PolyQ diseases lead to serious, constantly progressing dysfunctions of the nervous and/or muscular systems, and there currently exists no efficacious therapy for any of them. Recent studies have convincingly shown that mCAG-RNA can actively participate in the pathological process during the development of PolyQ diseases. Mutant RNA is involved in a wide range of molecular mechanisms, ultimately leading to disruption of the functions of transcription, splicing, translation, cytosol structure, RNA transport from the nucleus to the cytoplasm, and, finally, to neurodegeneration. This review discusses the involvement of mutant mCAG-RNA in neurodegenerative processes in PolyQ diseases.

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Funding

This work was supported by the Russian Science Foundation (project no. 19-15-00425).

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  1. Federal Research and Clinical Center of Physical-Chemical Medicine, Federal Medical Biological Agency, 119435, Moscow, Russia

    A. N. Bogomazova, A. V. Eremeev, G. E. Pozmogova & M. A. Lagarkova

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  1. A. N. Bogomazova
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  2. A. V. Eremeev
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  3. G. E. Pozmogova
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Translated by D. Timchenko

Abbreviations: GABA, gamma-aminobutyric acid; IPSC, induced pluripotent stem cells; ASO, antisense oligonucleotide; DM, myotonic dystrophy; DMPK, myotonic dystrophy protein kinase; DRPA, dentatorubral-pallidoluysian atrophy; FDA, Food and Drug Administration; FISH, fluorescence in situ hybridization; HTT, huntingtin protein; MBNL1, muscleblindlike splicing regulator 1; mCAG-RNA, mRNA with CAG repeat expansion; mCUG-RNA, mRNA with CUG expansion; mHTT, mutant huntingtin; MID1 (Midline 1), E3 ubiquitin-protein ligase Midline-1; OMIM, Online Mendelian Inheritance in Man; PolyQ, polyglutamine; PP2A, protein phosphatase 2A; RAN, repeat associated non-ATG; SBMA, spinal and bulbar muscular atrophy; SCA, spinocerebellar ataxia; sCAG, 21 bp-long RNA duplexes composed of CAG repeats.

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Bogomazova, A.N., Eremeev, A.V., Pozmogova, G.E. et al. The Role of Mutant RNA in the Pathogenesis of Huntington’s Disease and Other Polyglutamine Diseases. Mol Biol 53, 838–849 (2019). https://doi.org/10.1134/S0026893319060037

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