1. Myotonic dystrophy CTG expansion affects synaptic vesicle proteins, neurotransmission and mouse behaviour. : Synaptic dysfunction in myotonic dystrophy
- Author
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Takashi Kimura, Bulmaro Cisneros, Esther Steidl, F. Trovero, Elodie Marciniak, Arnold Munnich, Yasuhiro Suzuki, Luc Buée, Geneviève Gourdon, Bruno Buisson, Oscar Hernández-Hernández, Hélène Obriot, Friedrich Metzger, Stefanie Saenger, Maurice S. Swanson, Tohru Matsuura, Konstantinos Charizanis, Jean-Charles Bizot, Mário Gomes-Pereira, Guillaume Bassez, Sabrina Luilier, Caroline Chevarin, Géraldine Sicot, Sandrine Humez, Michel Hamon, Kuang-Yung Lee, Nicolas Sergeant, Aline Huguet, Céline Guiraud-Dogan, Annie Nicole, Lucile Revillod, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de pathologie [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Parc Technologique de la Source, Key-Obs, Neuroservice, Laboratoire privé, CNS Discovery Research, F. Hoffmann-La Roche [Basel], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Institut de psychiatrie et neurosciences (U894 / UMS 1266), Department of Molecular Genetics and Microbiology and the Center for NeuroGenetics, University of Florida [Gainesville] (UF), Department of Neurology, Chang Gung Memorial Hospital [Taipei] (CGMH), National Hospital Organization-Asahikawa Medical Center, Okayama University, Departamento de Génética y Biologia Molecular, Centro de Investigacion y de Estufios Avanzados del I.P.N., Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, Centre de Psychiatrie et Neurosciences ( CPN - U894 ), University of Florida [Gainesville], Chang Gung Memorial Hospital, Okayama University [Okayama], Institut Mondor de Recherche Biomédicale ( IMRB ), and Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 )
- Subjects
Genetically modified mouse ,Adult ,Male ,Synapsin I ,Central nervous system ,Blotting, Western ,Mice, Transgenic ,Biology ,Real-Time Polymerase Chain Reaction ,Myotonic dystrophy ,Synaptic Transmission ,Synapse ,03 medical and health sciences ,Mice ,0302 clinical medicine ,synapse ,medicine ,Animals ,Humans ,Electrophoresis, Gel, Two-Dimensional ,In Situ Hybridization, Fluorescence ,mouse ,030304 developmental biology ,Aged ,0303 health sciences ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,myotonic dystrophy ,Behavior, Animal ,Reverse Transcriptase Polymerase Chain Reaction ,Original Articles ,Middle Aged ,medicine.disease ,Myotonia ,central nervous system ,3. Good health ,Electrophysiology ,medicine.anatomical_structure ,Synaptic plasticity ,Neurology (clinical) ,Synaptic Vesicles ,[ SDV.GEN ] Life Sciences [q-bio]/Genetics ,Trinucleotide repeat expansion ,Trinucleotide Repeat Expansion ,Neuroscience ,030217 neurology & neurosurgery - Abstract
International audience; Myotonic dystrophy type 1 is a complex multisystemic inherited disorder, which displays multiple debilitating neurological manifestations. Despite recent progress in the understanding of the molecular pathogenesis of myotonic dystrophy type 1 in skeletal muscle and heart, the pathways affected in the central nervous system are largely unknown. To address this question, we studied the only transgenic mouse line expressing CTG trinucleotide repeats in the central nervous system. These mice recreate molecular features of RNA toxicity, such as RNA foci accumulation and missplicing. They exhibit relevant behavioural and cognitive phenotypes, deficits in short-term synaptic plasticity, as well as changes in neurochemical levels. In the search for disease intermediates affected by disease mutation, a global proteomics approach revealed RAB3A upregulation and synapsin I hyperphosphorylation in the central nervous system of transgenic mice, transfected cells and post-mortem brains of patients with myotonic dystrophy type 1. These protein defects were associated with electrophysiological and behavioural deficits in mice and altered spontaneous neurosecretion in cell culture. Taking advantage of a relevant transgenic mouse of a complex human disease, we found a novel connection between physiological phenotypes and synaptic protein dysregulation, indicative of synaptic dysfunction in myotonic dystrophy type 1 brain pathology.
- Published
- 2013
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