Publication Date:
2014-08-12
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mizielinska, Sarah -- Gronke, Sebastian -- Niccoli, Teresa -- Ridler, Charlotte E -- Clayton, Emma L -- Devoy, Anny -- Moens, Thomas -- Norona, Frances E -- Woollacott, Ione O C -- Pietrzyk, Julian -- Cleverley, Karen -- Nicoll, Andrew J -- Pickering-Brown, Stuart -- Dols, Jacqueline -- Cabecinha, Melissa -- Hendrich, Oliver -- Fratta, Pietro -- Fisher, Elizabeth M C -- Partridge, Linda -- Isaacs, Adrian M -- 089701/Wellcome Trust/United Kingdom -- 098565/Wellcome Trust/United Kingdom -- G0701441/Medical Research Council/United Kingdom -- G1000287/Medical Research Council/United Kingdom -- MR/J004022/1/Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2014 Sep 5;345(6201):1192-4. doi: 10.1126/science.1256800. Epub 2014 Aug 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK. ; Max Planck Institute for Biology of Ageing, 50931 Cologne, Germany. ; 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. ; 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. ; Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK. MRC Prion Unit, UCL Institute of Neurology, London WC1N 3BG, UK. ; Institute of Brain, Behaviour and Mental Health, Faculty of Human and Medical Sciences, University of Manchester, Manchester M13 9PT, UK. ; Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, University College London, London WC1E 6BT, UK. ; 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. ; 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. a.isaacs@prion.ucl.ac.uk l.partridge@ucl.ac.uk. ; Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK. a.isaacs@prion.ucl.ac.uk l.partridge@ucl.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25103406" target="_blank"〉PubMed〈/a〉
Keywords:
Amyotrophic Lateral Sclerosis/*genetics/pathology
;
Animals
;
Cell Line, Tumor
;
DNA Repeat Expansion/*genetics
;
Dipeptides/metabolism
;
Disease Models, Animal
;
Drosophila melanogaster/*genetics
;
Escherichia coli
;
Frontotemporal Dementia/*genetics/pathology
;
Humans
;
Neurons/metabolism/pathology
;
Proteins/*genetics
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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