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

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

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
Journal	Science (New York, N.Y.)
Volume	345
Issue number	6201
DOIs	https://doi.org/10.1126/science.1256800
Publication status	Published - 5 Sept 2014

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Dementia@Manchester

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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 (New York, N.Y.), 345(6201), 1192-1194. https://doi.org/10.1126/science.1256800

@article{665f9e5fa86c43ad88df7920eb3e8715,

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.",

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}",

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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 (New York, N.Y.), 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

N1 - 089701, Wellcome Trust, United Kingdom098565, Wellcome Trust, United Kingdom2615, Department of Health, United KingdomG0701441, Medical Research Council, United KingdomG1000287, Medical Research Council, United KingdomMR/J004022/1, Medical Research Council, United Kingdom, Medical Research Council, United Kingdom, Wellcome Trust, United Kingdom

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.

U2 - 10.1126/science.1256800

DO - 10.1126/science.1256800

M3 - Article

C2 - 25103406

VL - 345

SP - 1192

EP - 1194

JO - Science (New York, N.Y.)

JF - Science (New York, N.Y.)

IS - 6201

ER -

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

Abstract

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