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Neurotherapeutics

, Volume 11, Issue 4, pp 721–731 | Cite as

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

  • Michael G. Kearse
  • Peter K. ToddEmail author
Review

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.

Keywords

Fragile X Polyglutamine C9orf72 Translation initiation Myotonic dystrophy ALS 

Notes

Acknowledgments

We thank Hank Paulson for critical reading of this manuscript. Funding for this work was provided by the M-Cubed Initiative, the Department of Veterans Affairs (BLRD #11212652), the NIH (R01NS086810, K08NS069809 and P30-AG13283), and the Harris Professorship to PKT. Additional funding for this work was provided by the NIH (F32NS089124) to MGK.

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Supplementary material

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Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2014

Authors and Affiliations

  1. 1.Department of NeurologyUniversity of Michigan Medical SchoolAnn ArborUSA
  2. 2.Veterans Affairs Medical CenterAnn ArborUSA

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