RAN translation and frameshifting as translational challenges at simple repeats of human neurodegenerative disorders

Abstract

Repeat-associated disorders caused by expansions of short sequences have been classified as coding and noncoding and are thought to be caused by protein gain-of-function and RNA gain-of-function mechanisms, respectively. The boundary between such classifications has recently been blurred by the discovery of repeat-associated non-AUG (RAN) translation reported in spinocerebellar ataxia type 8, myotonic dystrophy type 1, fragile X tremor/ataxia syndrome and C9ORF72 amyotrophic lateral sclerosis and frontotemporal dementia. This noncanonical translation requires no AUG start codon and can initiate in multiple frames of CAG, CGG and GGGGCC repeats of the sense and antisense strands of disease-relevant transcripts. RNA structures formed by the repeats have been suggested as possible triggers; however, the precise mechanism of the translation initiation remains elusive. Templates containing expansions of microsatellites have also been shown to challenge translation elongation, as frameshifting has been recognized across CAG repeats in spinocerebellar ataxia type 3 and Huntington's disease. Determining the critical requirements for RAN translation and frameshifting is essential to decipher the mechanisms that govern these processes. The contribution of unusual translation products to pathogenesis needs to be better understood. In this review, we present current knowledge regarding RAN translation and frameshifting and discuss the proposed mechanisms of translational challenges imposed by simple repeat expansions.

RAN translation—What makes it run?

“…One further issue is whether frameshifting may also contribute to toxicity and inclusion burden in Huntington’s disease (Wojciechowska et al, 2014). Frameshifting from the polyglutamine reading frame into the polyalanine or polyserine reading frames has been suggested for a number of years as a potential mechanism for aspects of neurotoxicity in animal models of SCA3 and Huntington disease (Toulouse et al, 2005, Davies and Rubinsztein, 2006; Stochmanski et al , 2012; Girstmair et al , 2013).…”

Augmented genetic decoding: global, local and temporal alterations of decoding processes and codon meaning

“…Alternative translational initiation is a widespread phenomenon with important implications for gene expression. Many human genes contain evolutionarily conserved protein-coding non-AUG-initiated extensions in their 5′ leaders 184 , and repeat-associated non-AUG initiation is implicated in human neurodegenerative disorders [185][186][187] .…”

An Expanded CAG Repeat in Huntingtin Causes +1 Frameshifting

“…Expanded CAG repeat stretches, implicated in CAG repeat or polyglutamine (polyQ) 4 diseases (2), mediate Ϫ1 translational frameshifting, although the underlying mechanisms differ depending on the context surrounding repeat runs (5,6,10). Our earlier work shows that pathological expansion of the CAG repeats (Ͼ35 consecutive CAG codons) in huntingtin (Htt) exon 1, implicated in Huntington disease, involves stochastic Ϫ1 frameshifting within the CAG stretch that is triggered by limitation of the charged cognate glutaminyl-tRNA Gln CUG, although uncharged tRNA Gln CUG is plentiful (5).…”