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Repeat RNA expansion disorders of the nervous system: post-transcriptional mechanisms and therapeutic strategies.
Schwartz, Joshua L; Jones, Krysten Leigh; Yeo, Gene W.
Afiliación
  • Schwartz JL; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
  • Jones KL; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
  • Yeo GW; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Crit Rev Biochem Mol Biol ; 56(1): 31-53, 2021 02.
Article en En | MEDLINE | ID: mdl-33172304
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ataxia / Temblor / Atrofia Muscular Espinal / Procesamiento Postranscripcional del ARN / Enfermedad de Huntington / Expansión de Repetición de Trinucleótido / Demencia Frontotemporal / Síndrome del Cromosoma X Frágil / Esclerosis Amiotrófica Lateral / Distrofia Miotónica Límite: Animals / Humans Idioma: En Revista: Crit Rev Biochem Mol Biol Asunto de la revista: BIOLOGIA MOLECULAR / BIOQUIMICA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ataxia / Temblor / Atrofia Muscular Espinal / Procesamiento Postranscripcional del ARN / Enfermedad de Huntington / Expansión de Repetición de Trinucleótido / Demencia Frontotemporal / Síndrome del Cromosoma X Frágil / Esclerosis Amiotrófica Lateral / Distrofia Miotónica Límite: Animals / Humans Idioma: En Revista: Crit Rev Biochem Mol Biol Asunto de la revista: BIOLOGIA MOLECULAR / BIOQUIMICA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido