Mechanisms of repeat-associated non-AUG translation in neurological microsatellite expansion disorders.
RAN translation
microsatellite repeat expansion disorders
pathophysiology
Journal
Biochemical Society transactions
ISSN: 1470-8752
Titre abrégé: Biochem Soc Trans
Pays: England
ID NLM: 7506897
Informations de publication
Date de publication:
30 04 2021
30 04 2021
Historique:
received:
20
11
2020
revised:
20
02
2021
accepted:
23
02
2021
pubmed:
18
3
2021
medline:
29
1
2022
entrez:
17
3
2021
Statut:
ppublish
Résumé
Repeat-associated non-AUG (RAN) translation was discovered in 2011 in spinocerebellar ataxia type 8 (SCA8) and myotonic dystrophy type 1 (DM1). This non-canonical form of translation occurs in all reading frames from both coding and non-coding regions of sense and antisense transcripts carrying expansions of trinucleotide to hexanucleotide repeat sequences. RAN translation has since been reported in 7 of the 53 known microsatellite expansion disorders which mainly present with neurodegenerative features. RAN translation leads to the biosynthesis of low-complexity polymeric repeat proteins with aggregating and cytotoxic properties. However, the molecular mechanisms and protein factors involved in assembling functional ribosomes in absence of canonical AUG start codons remain poorly characterised while secondary repeat RNA structures play key roles in initiating RAN translation. Here, we briefly review the repeat expansion disorders, their complex pathogenesis and the mechanisms of physiological translation initiation together with the known factors involved in RAN translation. Finally, we discuss research challenges surrounding the understanding of pathogenesis and future directions that may provide opportunities for the development of novel therapeutic approaches for this group of incurable neurodegenerative diseases.
Identifiants
pubmed: 33729487
pii: 228089
doi: 10.1042/BST20200690
pmc: PMC8106499
doi:
Substances chimiques
Ataxins
0
Codon, Initiator
0
HTT protein, human
0
Huntingtin Protein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
775-792Subventions
Organisme : Medical Research Council
ID : MR/R024162/1
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/S005277/1
Pays : United Kingdom
Informations de copyright
© 2021 The Author(s).
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