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

Oscar Hernández-Hernández, Céline Guiraud-Dogan, Géraldine Sicot, Aline Huguet, Sabrina Luilier, Esther Steidl, Stefanie Saenger, Elodie Marciniak, Hélène Obriot, Caroline Chevarin, Annie Nicole, Lucile Revillod, Konstantinos Charizanis, Kuang Yung Lee, Yasuhiro Suzuki, Takashi Kimura, Tohru Matsuura, Bulmaro Cisneros, Maurice S. Swanson, Fabrice TroveroBruno Buisson, Jean Charles Bizot, Michel Hamon, Sandrine Humez, Guillaume Bassez, Friedrich Metzger, Luc Buée, Arnold Munnich, Nicolas Sergeant, Geneviève Gourdon, Mário Gomes-Pereira*

*此作品的通信作者

研究成果: 期刊稿件文章同行評審

62 引文 斯高帕斯(Scopus)

摘要

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.

原文英語
頁(從 - 到)957-970
頁數14
期刊Brain
136
發行號3
DOIs
出版狀態已出版 - 03 2013
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