C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins

Sarah Mizielinska; Sebastian Grönke; Teresa Niccoli; Charlotte E Ridler; Emma L Clayton; Anny Devoy; Thomas Moens; Frances E Norona; Ione O C Woollacott; Julian Pietrzyk; Karen Cleverley; Andrew J Nicoll; Stuart Pickering-Brown; Jacqueline Dols; Melissa Cabecinha; Oliver Hendrich; Pietro Fratta; Elizabeth M C Fisher; Linda Partridge; Adrian M Isaacs

doi:10.1126/science.1256800

C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins

Sarah Mizielinska, Sebastian Grönke, Teresa Niccoli, Charlotte E Ridler, Emma L Clayton, Anny Devoy, Thomas Moens, Frances E Norona, Ione O C Woollacott, Julian Pietrzyk, Karen Cleverley, Andrew J Nicoll, Stuart Pickering-Brown, Jacqueline Dols, Melissa Cabecinha, Oliver Hendrich, Pietro Fratta, Elizabeth M C Fisher, Linda Partridge, Adrian M Isaacs

Basic and Clinical Neuroscience

UCL University College London
Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, 50931, Cologne, Germany.
Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, UCL, Darwin Building, Gower Street, London WC1E 6BT, UK.
Institute of Brain, Behaviour and Mental Health, Faculty of Human and Medical Sciences, University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, UK.

Research output: Contribution to journal › Article › peer-review

539 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1192-1194
Number of pages	3
Journal	Science
Volume	345
Issue number	6201
Early online date	5 Sept 2014
DOIs	https://doi.org/10.1126/science.1256800
Publication status	Published - 5 Sept 2014

Keywords

Amyotrophic Lateral Sclerosis/genetics
Animals
C9orf72 Protein
Cell Line, Tumor
DNA Repeat Expansion/genetics
Dipeptides/metabolism
Disease Models, Animal
Drosophila melanogaster/genetics
Escherichia coli
Frontotemporal Dementia/genetics
Humans
Neurons/metabolism
Proteins/genetics

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10.1126/science.1256800

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Mizielinska, S., Grönke, S., Niccoli, T., Ridler, C. E., Clayton, E. L., Devoy, A., Moens, T., Norona, F. E., Woollacott, I. O. C., Pietrzyk, J., Cleverley, K., Nicoll, A. J., Pickering-Brown, S., Dols, J., Cabecinha, M., Hendrich, O., Fratta, P., Fisher, E. M. C., Partridge, L., & Isaacs, A. M. (2014). C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science, 345(6201), 1192-1194. https://doi.org/10.1126/science.1256800

@article{edc596431b07438eb40ab7d60548236f,

title = "C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins",

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. ",

keywords = "Amyotrophic Lateral Sclerosis/genetics, Animals, C9orf72 Protein, Cell Line, Tumor, DNA Repeat Expansion/genetics, Dipeptides/metabolism, Disease Models, Animal, Drosophila melanogaster/genetics, Escherichia coli, Frontotemporal Dementia/genetics, Humans, Neurons/metabolism, Proteins/genetics",

author = "Sarah Mizielinska and Sebastian Gr{\"o}nke and Teresa Niccoli and Ridler, {Charlotte E} and Clayton, {Emma L} and Anny Devoy and Thomas Moens and Norona, {Frances E} and Woollacott, {Ione O C} and Julian Pietrzyk and Karen Cleverley and Nicoll, {Andrew J} and Stuart Pickering-Brown and Jacqueline Dols and Melissa Cabecinha and Oliver Hendrich and Pietro Fratta and Fisher, {Elizabeth M C} and Linda Partridge and Isaacs, {Adrian M}",

note = "Copyright {\textcopyright} 2014, American Association for the Advancement of Science.",

year = "2014",

month = sep,

day = "5",

doi = "10.1126/science.1256800",

language = "English",

volume = "345",

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Mizielinska, S, Grönke, S, Niccoli, T, Ridler, CE, Clayton, EL, Devoy, A, Moens, T, Norona, FE, Woollacott, IOC, Pietrzyk, J, Cleverley, K, Nicoll, AJ, Pickering-Brown, S, Dols, J, Cabecinha, M, Hendrich, O, Fratta, P, Fisher, EMC, Partridge, L & Isaacs, AM 2014, 'C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins', Science, vol. 345, no. 6201, pp. 1192-1194. https://doi.org/10.1126/science.1256800

TY - JOUR

T1 - C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins

AU - Mizielinska, Sarah

AU - Grönke, Sebastian

AU - Niccoli, Teresa

AU - Ridler, Charlotte E

AU - Clayton, Emma L

AU - Devoy, Anny

AU - Moens, Thomas

AU - Norona, Frances E

AU - Woollacott, Ione O C

AU - Pietrzyk, Julian

AU - Cleverley, Karen

AU - Nicoll, Andrew J

AU - Pickering-Brown, Stuart

AU - Dols, Jacqueline

AU - Cabecinha, Melissa

AU - Hendrich, Oliver

AU - Fratta, Pietro

AU - Fisher, Elizabeth M C

AU - Partridge, Linda

AU - Isaacs, Adrian M

PY - 2014/9/5

Y1 - 2014/9/5

N2 - 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.

AB - 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.

KW - Amyotrophic Lateral Sclerosis/genetics

KW - Animals

KW - C9orf72 Protein

KW - Cell Line, Tumor

KW - DNA Repeat Expansion/genetics

KW - Dipeptides/metabolism

KW - Disease Models, Animal

KW - Drosophila melanogaster/genetics

KW - Escherichia coli

KW - Frontotemporal Dementia/genetics

KW - Humans

KW - Neurons/metabolism

KW - Proteins/genetics

U2 - 10.1126/science.1256800

DO - 10.1126/science.1256800

M3 - Article

C2 - 25103406

SN - 0036-8075

VL - 345

SP - 1192

EP - 1194

JO - Science

JF - Science

IS - 6201

ER -

C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins

Abstract

Keywords

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