Translation of Expanded CGG Repeats into FMRpolyG Is Pathogenic and May Contribute to Fragile X Tremor Ataxia Syndrome

Chantal Sellier; Ronald A M Buijsen; Fang He; Sam Natla; Laura Jung; Philippe Tropel; Angeline Gaucherot; Hugues Jacobs; Hamid Meziane; Alexandre Vincent; Marie France Champy; Tania Sorg; Guillaume Pavlovic; Marie Wattenhofer-Donze; Marie Christine Birling; Mustapha Oulad-Abdelghani; Pascal Eberling; Frank Ruffenach; Mathilde Joint; Mathieu Anheim; Veronica Martinez-Cerdeno; Flora Tassone; Rob Willemsen; Renate K. Hukema; Stéphane Viville; Cecile Martinat; Peter K. Todd; Nicolas Charlet-Berguerand

doi:10.1016/j.neuron.2016.12.016

Translation of Expanded CGG Repeats into FMRpolyG Is Pathogenic and May Contribute to Fragile X Tremor Ataxia Syndrome

Chantal Sellier, Ronald A M Buijsen, Fang He, Sam Natla, Laura Jung, Philippe Tropel, Angeline Gaucherot, Hugues Jacobs, Hamid Meziane, Alexandre Vincent, Marie France Champy, Tania Sorg, Guillaume Pavlovic, Marie Wattenhofer-Donze, Marie Christine Birling, Mustapha Oulad-Abdelghani, Pascal Eberling, Frank Ruffenach, Mathilde Joint, Mathieu AnheimVeronica Martinez-Cerdeno, Flora Tassone, Rob Willemsen, Renate K. Hukema, Stéphane Viville, Cecile Martinat, Peter K. Todd, Nicolas Charlet-Berguerand

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

94 Scopus citations

Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a limited expansion of CGG repeats in the 5′ UTR of FMR1. Two mechanisms are proposed to cause FXTAS: RNA gain-of-function, where CGG RNA sequesters specific proteins, and translation of CGG repeats into a polyglycine-containing protein, FMRpolyG. Here we developed transgenic mice expressing CGG repeat RNA with or without FMRpolyG. Expression of FMRpolyG is pathogenic, while the sole expression of CGG RNA is not. FMRpolyG interacts with the nuclear lamina protein LAP2β and disorganizes the nuclear lamina architecture in neurons differentiated from FXTAS iPS cells. Finally, expression of LAP2β rescues neuronal death induced by FMRpolyG. Overall, these results suggest that translation of expanded CGG repeats into FMRpolyG alters nuclear lamina architecture and drives pathogenesis in FXTAS.

Original language	English (US)
Pages (from-to)	331-347
Number of pages	17
Journal	Neuron
Volume	93
Issue number	2
DOIs	https://doi.org/10.1016/j.neuron.2016.12.016
State	Published - Jan 18 2017

Keywords

microsatellite expansion
near-cognate codon
neurodegeneration
RAN translation

ASJC Scopus subject areas

Neuroscience(all)

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10.1016/j.neuron.2016.12.016

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Sellier, C., Buijsen, R. A. M., He, F., Natla, S., Jung, L., Tropel, P., Gaucherot, A., Jacobs, H., Meziane, H., Vincent, A., Champy, M. F., Sorg, T., Pavlovic, G., Wattenhofer-Donze, M., Birling, M. C., Oulad-Abdelghani, M., Eberling, P., Ruffenach, F., Joint, M., ... Charlet-Berguerand, N. (2017). Translation of Expanded CGG Repeats into FMRpolyG Is Pathogenic and May Contribute to Fragile X Tremor Ataxia Syndrome. Neuron, 93(2), 331-347. https://doi.org/10.1016/j.neuron.2016.12.016

Translation of Expanded CGG Repeats into FMRpolyG Is Pathogenic and May Contribute to Fragile X Tremor Ataxia Syndrome. / Sellier, Chantal; Buijsen, Ronald A M; He, Fang; Natla, Sam; Jung, Laura; Tropel, Philippe; Gaucherot, Angeline; Jacobs, Hugues; Meziane, Hamid; Vincent, Alexandre; Champy, Marie France; Sorg, Tania; Pavlovic, Guillaume; Wattenhofer-Donze, Marie; Birling, Marie Christine; Oulad-Abdelghani, Mustapha; Eberling, Pascal; Ruffenach, Frank; Joint, Mathilde; Anheim, Mathieu; Martinez-Cerdeno, Veronica ; Tassone, Flora; Willemsen, Rob; Hukema, Renate K.; Viville, Stéphane; Martinat, Cecile; Todd, Peter K.; Charlet-Berguerand, Nicolas.

In: Neuron, Vol. 93, No. 2, 18.01.2017, p. 331-347.

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

Sellier, C, Buijsen, RAM, He, F, Natla, S, Jung, L, Tropel, P, Gaucherot, A, Jacobs, H, Meziane, H, Vincent, A, Champy, MF, Sorg, T, Pavlovic, G, Wattenhofer-Donze, M, Birling, MC, Oulad-Abdelghani, M, Eberling, P, Ruffenach, F, Joint, M, Anheim, M, Martinez-Cerdeno, V , Tassone, F, Willemsen, R, Hukema, RK, Viville, S, Martinat, C, Todd, PK & Charlet-Berguerand, N 2017, 'Translation of Expanded CGG Repeats into FMRpolyG Is Pathogenic and May Contribute to Fragile X Tremor Ataxia Syndrome', Neuron, vol. 93, no. 2, pp. 331-347. https://doi.org/10.1016/j.neuron.2016.12.016

Sellier, Chantal ; Buijsen, Ronald A M ; He, Fang ; Natla, Sam ; Jung, Laura ; Tropel, Philippe ; Gaucherot, Angeline ; Jacobs, Hugues ; Meziane, Hamid ; Vincent, Alexandre ; Champy, Marie France ; Sorg, Tania ; Pavlovic, Guillaume ; Wattenhofer-Donze, Marie ; Birling, Marie Christine ; Oulad-Abdelghani, Mustapha ; Eberling, Pascal ; Ruffenach, Frank ; Joint, Mathilde ; Anheim, Mathieu ; Martinez-Cerdeno, Veronica ; Tassone, Flora ; Willemsen, Rob ; Hukema, Renate K. ; Viville, Stéphane ; Martinat, Cecile ; Todd, Peter K. ; Charlet-Berguerand, Nicolas. / Translation of Expanded CGG Repeats into FMRpolyG Is Pathogenic and May Contribute to Fragile X Tremor Ataxia Syndrome. In: Neuron. 2017 ; Vol. 93, No. 2. pp. 331-347.

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abstract = "Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a limited expansion of CGG repeats in the 5′ UTR of FMR1. Two mechanisms are proposed to cause FXTAS: RNA gain-of-function, where CGG RNA sequesters specific proteins, and translation of CGG repeats into a polyglycine-containing protein, FMRpolyG. Here we developed transgenic mice expressing CGG repeat RNA with or without FMRpolyG. Expression of FMRpolyG is pathogenic, while the sole expression of CGG RNA is not. FMRpolyG interacts with the nuclear lamina protein LAP2β and disorganizes the nuclear lamina architecture in neurons differentiated from FXTAS iPS cells. Finally, expression of LAP2β rescues neuronal death induced by FMRpolyG. Overall, these results suggest that translation of expanded CGG repeats into FMRpolyG alters nuclear lamina architecture and drives pathogenesis in FXTAS.",

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AU - Natla, Sam

AU - Jung, Laura

AU - Tropel, Philippe

AU - Gaucherot, Angeline

AU - Jacobs, Hugues

AU - Meziane, Hamid

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AU - Champy, Marie France

AU - Sorg, Tania

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AU - Ruffenach, Frank

AU - Joint, Mathilde

AU - Anheim, Mathieu

AU - Martinez-Cerdeno, Veronica

AU - Tassone, Flora

AU - Willemsen, Rob

AU - Hukema, Renate K.

AU - Viville, Stéphane

AU - Martinat, Cecile

AU - Todd, Peter K.

AU - Charlet-Berguerand, Nicolas

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N2 - Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a limited expansion of CGG repeats in the 5′ UTR of FMR1. Two mechanisms are proposed to cause FXTAS: RNA gain-of-function, where CGG RNA sequesters specific proteins, and translation of CGG repeats into a polyglycine-containing protein, FMRpolyG. Here we developed transgenic mice expressing CGG repeat RNA with or without FMRpolyG. Expression of FMRpolyG is pathogenic, while the sole expression of CGG RNA is not. FMRpolyG interacts with the nuclear lamina protein LAP2β and disorganizes the nuclear lamina architecture in neurons differentiated from FXTAS iPS cells. Finally, expression of LAP2β rescues neuronal death induced by FMRpolyG. Overall, these results suggest that translation of expanded CGG repeats into FMRpolyG alters nuclear lamina architecture and drives pathogenesis in FXTAS.

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Translation of Expanded CGG Repeats into FMRpolyG Is Pathogenic and May Contribute to Fragile X Tremor Ataxia Syndrome

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