Repeat-Associated Non-AUG Translation and Its Impact in Neurodegenerative Disease

Abstract

Nucleotide repeat expansions underlie numerous human neurological disorders. Repeats can trigger toxicity through multiple pathogenic mechanisms, including RNA gain-of-function, protein gain-of-function, and protein loss-of-function pathways. Traditionally, inference of the underlying pathogenic mechanism derives from the repeat location, with dominantly inherited repeats within transcribed noncoding sequences eliciting toxicity predominantly as RNA via sequestration of specific RNA binding proteins. However, recent findings question this assumption and suggest that repeats outside of annotated open reading frames may also trigger toxicity through a novel form of protein translational initiation known as repeat-associated non-AUG (RAN) translation. To date, RAN translation has been implicated in 4 nucleotide repeat expansion disorders: spinocerebellar ataxia type 8; myotonic dystrophy type 1 with CTG•CAG repeats; C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia with GGGGCC•GGCCCC repeats; and fragile X-associated tremor/ataxia syndrome with CGG repeats. RAN translation contributes to hallmark pathological characteristics in these disorders by producing homopolymeric or dipeptide repeat proteins. Here, we review what is known about RAN translation, with an emphasis on how differences in both repeat sequence and context may confer different requirements for unconventional initiation. We then discuss how this new mechanism of translational initiation might function in normal physiology and lay out a roadmap for addressing the numerous questions that remain.

Molecular Analysis of CTG/CTA Repeats at SCA8 Locus in South Indian Population

“…Some individuals present with nystagmus, dysmetric saccades and, rarely, ophthalmoplegia. Tendon reflex hyperreflexity and extensor plantar responses are present in some severely affected individuals [15]. In the present study >35 repeats were found only in patients only with clinical symptoms of SCA 8 type (Table 2).…”

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

“…A tremendous amount of effort has gone into defining several nonmutually exclusive disease mechanisms suggested by this mutation (Haeusler et al 2016;Taylor et al 2016), yet the relative contributions of each mutation are unclear in vivo. C9 ALS/FTD is similar to most other forms of ALS in that it is marked by TDP-43 pathology but also has a distinct class of Ub + /p62 + cytoplasmic inclusions containing dipeptide repeat (DPR) proteins made by RAN translation (Kearse and Todd 2014;Schipper et al 2016). Why C9 causes some people to get pure ALS or FTD or a mixture of both is a mystery.…”

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] .…”