Translation of Expanded CGG Repeats into FMRpolyG Is Pathogenic and May Contribute to Fragile X Tremor Ataxia Syndrome
| Autor: | Marie-Christine Birling, Chantal Sellier, Frank Ruffenach, Cécile Martinat, Marie Wattenhofer-Donzé, Stéphane Viville, Ronald A.M. Buijsen, Mustapha Oulad-Abdelghani, Hamid Meziane, Peter K. Todd, Alexandre Vincent, Guillaume Pavlovic, Pascal Eberling, Hugues Jacobs, Verónica Martínez-Cerdeño, Flora Tassone, Marie-France Champy, Laura Jung, Fang He, Nicolas Charlet-Berguerand, Philippe Tropel, Mathieu Anheim, Angeline Gaucherot, Tania Sorg, Renate K. Hukema, Mathilde Joint, Rob Willemsen, Sam Natla |
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| Přispěvatelé: | Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Michigan [Ann Arbor], University of Michigan System, Institut Clinique de la Souris (ICS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Hôpital de Hautepierre [Strasbourg], University of California [Davis] (UC Davis), University of California, Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Nouvel Hôpital Civil de Strasbourg, Institut de Parasitologie et de Pathologie Tropicale (IPPTS), Université de Strasbourg (UNISTRA), Université d'Évry-Val-d'Essonne (UEVE), Institut des cellules souches pour le traitement et l'étude des maladies monogéniques (I-STEM), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, Association française contre les myopathies (AFM-Téléthon), Centre for Integrative Biology - CBI (Inserm U964 - CNRS UMR7104 - IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), French National Infrastructure for Mouse Phenogenomics (PHENOMIN), CHU Strasbourg, University of California (UC), Dieterle, Stéphane, Clinical Genetics |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Untranslated region MESH: Ataxia [SDV]Life Sciences [q-bio] MESH: Tremor MESH: Nuclear Lamina Pathogenesis Fragile X Mental Retardation Protein Mice [SCCO]Cognitive science Tremor MESH: Trinucleotide Repeat Expansion MESH: Animals Induced pluripotent stem cell ComputingMilieux_MISCELLANEOUS Genetics Fragile X Tremor/Ataxia Syndrome MESH: Peptides MESH: Real-Time Polymerase Chain Reaction General Neuroscience neurodegeneration Brain Translation (biology) 3. Good health DNA-Binding Proteins [SDV] Life Sciences [q-bio] MESH: Protein Biosynthesis Nuclear lamina MESH: Membrane Proteins MESH: Fragile X Syndrome medicine.symptom congenital hereditary and neonatal diseases and abnormalities near-cognate codon Ataxia MESH: Mice Transgenic Neuroscience(all) Mice Transgenic Biology Real-Time Polymerase Chain Reaction MESH: Fragile X Mental Retardation Protein Article MESH: Brain 03 medical and health sciences RAN translation medicine Animals Humans RNA Messenger MESH: Mice MESH: RNA Messenger Nuclear Lamina MESH: Humans Membrane Proteins RNA [SCCO] Cognitive science microsatellite expansion MESH: Male nervous system diseases 030104 developmental biology Fragile X Syndrome Protein Biosynthesis Peptides Trinucleotide Repeat Expansion MESH: DNA-Binding Proteins |
| Zdroj: | Neuron Neuron, Elsevier, 2017, 93 (2), pp.331-347. ⟨10.1016/j.neuron.2016.12.016⟩ Neuron, 2017, 93 (2), pp.331-347. ⟨10.1016/j.neuron.2016.12.016⟩ Neuron, 93(2), 331-347. Cell Press |
| ISSN: | 0896-6273 |
| DOI: | 10.1016/j.neuron.2016.12.016⟩ |
| Popis: | Summary 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. Highlights • CGG repeats in the 5′ UTR of FMR1 are translated through initiation to an ACG codon • Translation of CGG repeats in the polyglycine protein, FMRpolyG, is toxic in mice • FMRpolyG binds and disrupts protein of the nuclear lamina Sellier et al. show that translation of expanded CGG repeats located in the 5′ UTR of the FMR1 gene require an upstream ACG near-cognate initiation codon. Translation of CGG repeats into a short polyglycine-containing protein, FMRpolyG, is pathogenic in mouse models. |
| Databáze: | OpenAIRE |
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