Abstract
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.
Highlights
Microsatellite expansions have been characterised in a large number of incurable neurodegenerative diseases subdivided into polyglutamine and non-polyglutamine disorders [1]
These most commonly include: CGG repeats in fragile X mental retardation 1 (FMR1) gene in Fragile X-associated syndromes [6]; thousands of CTG/CCTG repeats in the myotonic dystrophies (DM1 and DM2) [7,8] and trinucleotide, pentanucleotide or hexanucleotide repeats in non-polyQ spinocerebellar ataxias (SCA) [9]; GAA repeat expansions in Friedreich’s ataxia [10]; thousands of GGGGCC repeats in chromosome 9 open reading frame 72 (C9ORF72) in the most common genetic forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) [11,12]
Protein loss-of-functions have been implicated in a wide range of expansion disorders via RNA-repeat sequestration of mRNA-binding proteins which may loose their normal cellular functions including: muscleblind-like splicing regulator (MBLN) and CUG-binding protein and ETR3-like factor (CELF) families of proteins in myotonic dystrophy [34,35,36]; MBLN and other RNA-binding proteins in polyQ disorders [37,38]; Sam68 [39], PUR-alpha, hnRNP A2/B1, CUGBP1 [40,41] in fragile X-associated tremor ataxia syndrome (FXTAS); PUR-alpha, heterogeneous nuclear ribonucleoproteins and SR-rich splicing factors (SRSFs) among others in C9ORF72-ALS/FTD [42,43]
Summary
Microsatellite expansions have been characterised in a large number of incurable neurodegenerative diseases subdivided into polyglutamine ( polyQ) and non-polyglutamine (non-polyQ) disorders [1]. A contributory loss-of-function is the likely pathological cause of diseases where the repeat expansions are found in promotors, e.g. fragile-XE mental retardation (FMR2 gene; [17]) and myoclonus epilepsy of the Unverricht-Lundborg type (CYSTB gene; [18]).
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