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Dipeptide repeat peptides on the attack

Certain neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), are associated with expanded dipeptides translated from RNA transcripts of disease-associated genes (see the Perspective by West and Gitler). Kwon et al. show that the peptides encoded by the expanded repeats in the C9orf72 gene interfere with the way cells make RNA and kill cells. These effects may account for how this genetic form of ALS causes disease. Working in Drosophila, Mizielinska et al. aimed to distinguish between the effects of repeat-containing RNAs and the dipeptide repeat peptides that they encode. The findings provide evidence that dipeptide repeat proteins can cause toxicity directly.
Science, this issue p. 1139 and p. 1192; see also p. 1118

Abstract

An expanded GGGGCC repeat in C9orf72 is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. A fundamental question is whether toxicity is driven by the repeat RNA itself and/or by dipeptide repeat proteins generated by repeat-associated, non-ATG translation. To address this question, we developed in vitro and in vivo models to dissect repeat RNA and dipeptide repeat protein toxicity. Expression of pure repeats, but not stop codon–interrupted “RNA-only” repeats in Drosophila caused adult-onset neurodegeneration. Thus, expanded repeats promoted neurodegeneration through dipeptide repeat proteins. Expression of individual dipeptide repeat proteins with a non-GGGGCC RNA sequence revealed that both poly-(glycine-arginine) and poly-(proline-arginine) proteins caused neurodegeneration. These findings are consistent with a dual toxicity mechanism, whereby both arginine-rich proteins and repeat RNA contribute to C9orf72-mediated neurodegeneration.

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Supplementary Material

Summary

Materials and Methods
Figs. S1 to S7
References (3235)

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References and Notes

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Science
Volume 345 | Issue 6201
5 September 2014

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Received: 2 June 2014
Accepted: 28 July 2014
Published in print: 5 September 2014

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Acknowledgments

We thank J. Wadsworth and N. Alic for helpful discussion. Funding was provided by Alzheimer’s Research UK (A.M.I.), the Motor Neurone Disease Association (A.M.I., E.M.C.F., P.F.), the Middlesex Hospital and Medical School General Charitable Trust (A.M.I.), National Institute for Health Research (NIHR)/University College London Hospitals Biomedical Research Centre (P.F.), BRT (T.M.), a NIHR Academic Clinical Fellowship (I.O.C.W.), the UK Medical Research Council (A.M.I., E.M.C.F., P.F.), the Wellcome Trust (L.P.), and the Max Planck Society (L.P.). Clones from the Isaacs lab will be distributed under material transfer agreements for academic use. L.P. dedicates this work to the memory of Noreen Murray.

Authors

Affiliations

Sarah Mizielinska*
Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK.
Sebastian Grönke*
Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.
Teresa Niccoli*
Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.
Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, University College London, London WC1E 6BT, UK.
Charlotte E. Ridler
Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK.
Emma L. Clayton
Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK.
Anny Devoy
Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK.
Thomas Moens
Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK.
Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, University College London, London WC1E 6BT, UK.
Frances E. Norona
Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK.
Ione O. C. Woollacott
Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK.
Julian Pietrzyk
Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK.
Karen Cleverley
Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK.
Andrew J. Nicoll
Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK.
MRC Prion Unit, UCL Institute of Neurology, London WC1N 3BG, UK.
Stuart Pickering-Brown
Institute of Brain, Behaviour and Mental Health, Faculty of Human and Medical Sciences, University of Manchester, Manchester M13 9PT, UK.
Jacqueline Dols
Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.
Melissa Cabecinha
Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, University College London, London WC1E 6BT, UK.
Oliver Hendrich
Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.
Pietro Fratta
Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK.
MRC Centre for Neuromuscular Disease, UCL Institute of Neurology, London WC1N 3BG, UK.
Elizabeth M. C. Fisher
Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK.
MRC Centre for Neuromuscular Disease, UCL Institute of Neurology, London WC1N 3BG, UK.
Linda Partridge [email protected]
Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany.
Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, University College London, London WC1E 6BT, UK.
Adrian M. Isaacs [email protected]
Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK.

Notes

*
These authors contributed equally to this work.
Corresponding author. E-mail: [email protected] (A.M.I.); [email protected] (L.P.)

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