TY - JOUR
T1 - Myotonic dystrophy CTG expansion affects synaptic vesicle proteins, neurotransmission and mouse behaviour
AU - Hernández-Hernández, Oscar
AU - Guiraud-Dogan, Céline
AU - Sicot, Géraldine
AU - Huguet, Aline
AU - Luilier, Sabrina
AU - Steidl, Esther
AU - Saenger, Stefanie
AU - Marciniak, Elodie
AU - Obriot, Hélène
AU - Chevarin, Caroline
AU - Nicole, Annie
AU - Revillod, Lucile
AU - Charizanis, Konstantinos
AU - Lee, Kuang Yung
AU - Suzuki, Yasuhiro
AU - Kimura, Takashi
AU - Matsuura, Tohru
AU - Cisneros, Bulmaro
AU - Swanson, Maurice S.
AU - Trovero, Fabrice
AU - Buisson, Bruno
AU - Bizot, Jean Charles
AU - Hamon, Michel
AU - Humez, Sandrine
AU - Bassez, Guillaume
AU - Metzger, Friedrich
AU - Buée, Luc
AU - Munnich, Arnold
AU - Sergeant, Nicolas
AU - Gourdon, Geneviève
AU - Gomes-Pereira, Mário
PY - 2013/3
Y1 - 2013/3
N2 - 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.
AB - 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.
KW - RAB3A
KW - myotonic dystrophy
KW - synapsin I
KW - synaptic transmission
KW - transgenic mice
UR - http://www.scopus.com/inward/record.url?scp=84874916176&partnerID=8YFLogxK
U2 - 10.1093/brain/aws367
DO - 10.1093/brain/aws367
M3 - 文章
AN - SCOPUS:84874916176
SN - 0006-8950
VL - 136
SP - 957
EP - 970
JO - Brain
JF - Brain
IS - 3
ER -