Myotonic dystrophy CTG expansion affects synaptic vesicle proteins, neurotransmission and mouse behaviour

• Published in: Brain (London, England : 1878) England : 1878), 2013-03, Vol.136 (Pt 3), p.957-970
• Main Authors: HERNANDEZ-HERNANDEZ, Oscar, GUIRAUD-DOGAN, Céline, NICOLE, Annie, REVILLOD, Lucile, CHARIZANIS, Konstantinos, LEE, Kuang-Yung, SUZUKI, Yasuhiro, KIMURA, Takashi, MATSUURA, Tohru, CISNEROS, Bulmaro, SWANSON, Maurice S, TROVERO, Fabrice, SICOT, Géraldine, BUISSON, Bruno, BIZOT, Jean-Charles, HAMON, Michel, HUMEZ, Sandrine, BASSEZ, Guillaume, METZGER, Friedrich, BUEE, Luc, MUNNICH, Arnold, SERGEANT, Nicolas, GOURDON, Geneviève, HUGUET, Aline, GOMES-PEREIRA, Mario, LUILIER, Sabrina, STEIDL, Esther, SAENGER, Stefanie, MARCINIAK, Elodie, OBRIOT, Hélène, CHEVARIN, Caroline
• Format: Article
• Language: English
• Subjects: Adult; Aged; Animals; Behavior, Animal - physiology; Biological and medical sciences; Blotting, Western; Brain; Cardiac muscle; Cell culture; Central nervous system; Cognitive ability; Diseases of striated muscles. Neuromuscular diseases; Electrophoresis, Gel, Two-Dimensional; Electrophysiology; Hereditary diseases; Humans; In Situ Hybridization, Fluorescence; Male; Medical sciences; Mice; Mice, Transgenic; Middle Aged; Mutation; Myotonic dystrophy; Myotonic Dystrophy - complications; Myotonic Dystrophy - genetics; Myotonic Dystrophy - metabolism; Neurology; Neurotransmission; Original; Phosphorylation; Plasticity (synaptic); proteomics; rab3A protein; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA; Skeletal muscle; Synaptic Transmission - physiology; Synaptic vesicles; Synaptic Vesicles - metabolism; Toxicity; Transgenic mice; trinucleotide repeat diseases; Trinucleotide Repeat Expansion
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/aws367

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.