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

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.

• Authors: 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
• Journal: Neuron (Neuron) Vol. 93 Issue 2 Pg. 331-347 (Jan 18 2017) ISSN: 1097-4199 [Electronic] United States
• PMID: 28065649 (Publication Type: Journal Article, Video-Audio Media)
• Copyright: Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• DNA-Binding Proteins
• FMR1 protein, human
• Membrane Proteins
• Peptides
• RNA, Messenger
• lamina-associated polypeptide 2
• Fragile X Mental Retardation Protein
• polyglycine

Topics

• Animals
• Ataxia (genetics, metabolism)
• Brain (metabolism, pathology)
• DNA-Binding Proteins (metabolism)
• Fragile X Mental Retardation Protein (genetics, metabolism)
• Fragile X Syndrome (genetics, metabolism)
• Humans
• Male
• Membrane Proteins (metabolism)
• Mice
• Mice, Transgenic
• Nuclear Lamina (metabolism, pathology)
• Peptides (genetics, metabolism)
• Protein Biosynthesis
• RNA, Messenger (metabolism)
• Real-Time Polymerase Chain Reaction
• Tremor (genetics, metabolism)
• Trinucleotide Repeat Expansion (genetics)