期刊
BRAIN
卷 136, 期 -, 页码 957-970出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/aws367
关键词
myotonic dystrophy; transgenic mice; synaptic transmission; RAB3A; synapsin I
资金
- ANR (Agence Nationale de Recherche, France)
- AFM (Association Francaise contre les Myopathies, France)
- Prosensa (The Netherlands)
- INSERM (Institute National de la Sante et Recherche Medicale, France)
- Universite Paris Descartes (Paris, France)
- CONACyT (Consejo Nacional de Ciencia y Tecnologia, Mexico)
- Ministe re Francais de la Recherche et Technologie
- NIH (National Institutes of Health) [AR046799, NS058901]
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.
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