Repeat RNA expansion disorders of the nervous system: post-transcriptional mechanisms and therapeutic strategies
| Autor: | Gene W. Yeo, Joshua L. Schwartz, Krysten Leigh Jones |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Transcription
Genetic repeat expansion rCas Bioinformatics Biochemistry Myotonic dystrophy Article Transcriptome ASO Muscular Atrophy Spinal 03 medical and health sciences C9orf72 RAN translation Tremor Medicine Animals Humans Myotonic Dystrophy Molecular Targeted Therapy RNA Messenger Amyotrophic lateral sclerosis RNA Processing Post-Transcriptional Molecular Biology 030304 developmental biology Neurons 0303 health sciences business.industry 030302 biochemistry & molecular biology RNA foci Amyotrophic Lateral Sclerosis RNA medicine.disease FMR1 Huntington Disease MRE Fragile X Syndrome Frontotemporal Dementia Protein Biosynthesis Ataxia business Trinucleotide repeat expansion protein Trinucleotide Repeat Expansion Frontotemporal dementia |
| Zdroj: | Critical reviews in biochemistry and molecular biology |
| ISSN: | 1549-7798 1040-9238 |
| Popis: | Dozens of incurable neurological disorders result from expansion of short repeat sequences in both coding and non-coding regions of the transcriptome. Short repeat expansions underlie microsatellite repeat expansion (MRE) disorders including myotonic dystrophy (DM1, CUG50-3,500 in DMPK; DM2, CCTG75-11,000 in ZNF9), fragile X tremor ataxia syndrome (FXTAS, CGG50-200 in FMR1), spinal bulbar muscular atrophy (SBMA, CAG40-55 in AR), Huntington's disease (HD, CAG36-121 in HTT), C9ORF72- amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD and C9-ALS/FTD, GGGGCC in C9ORF72), and many others, like ataxias. Recent research has highlighted several mechanisms that may contribute to pathology in this heterogeneous class of neurological MRE disorders - bidirectional transcription, intranuclear RNA foci, and repeat associated non-AUG (RAN) translation - which are the subject of this review. Additionally, many MRE disorders share similar underlying molecular pathologies that have been recently targeted in experimental and preclinical contexts. We discuss the therapeutic potential of versatile therapeutic strategies that may selectively target disrupted RNA-based processes and may be readily adaptable for the treatment of multiple MRE disorders. Collectively, the strategies under consideration for treatment of multiple MRE disorders include reducing levels of toxic RNA, preventing RNA foci formation, and eliminating the downstream cellular toxicity associated with peptide repeats produced by RAN translation. While treatments are still lacking for the majority of MRE disorders, several promising therapeutic strategies have emerged and will be evaluated within this review. |
| Databáze: | OpenAIRE |
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