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 journalArticle

76 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 languageEnglish (US)
Pages (from-to)331-347
Number of pages17
JournalNeuron
Volume93
Issue number2
DOIs
StatePublished - Jan 18 2017

Keywords

  • microsatellite expansion
  • near-cognate codon
  • neurodegeneration
  • RAN translation

ASJC Scopus subject areas

  • Neuroscience(all)

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