title: Synaptic protein dysregulation in myotonic dystrophy type 1: Disease neuropathogenesis beyond missplicing.
abstract: The toxicity of expanded transcripts in myotonic dystrophy type 1 (DM1) is mainly mediated by the disruption of alternative splicing. However, the detailed disease mechanisms in the central nervous system (CNS) have not been fully elucidated. In our recent study, we demonstrated that the accumulation of mutant transcripts in the CNS of a mouse model of DM1 disturbs splicing in a region-specific manner. We now discuss that the spatial- and temporal-regulated expression of splicing factors may contribute to the region-specific spliceopathy in DM1 brains. In the search for disease mechanisms operating in the CNS, we found that the expression of expanded CUG-containing RNA affects the expression and phosphorylation of synaptic vesicle proteins, possibly contributing to DM1 neurological phenotypes. Although mediated by splicing regulators with a described role in DM1, the misregulation of synaptic proteins was not associated with missplicing of their coding transcripts, supporting the view that DM1 mechanisms in the CNS have also far-reaching implications beyond the disruption of a splicing program.
authors.affiliation: Inserm U781; Hôpital Necker Enfants Malades; Paris, France ; Laboratorio de Medicina Genómica; Departamento de Genética; Instituto Nacional de Rehabilitación; Calzada México Xochimilco, México.
authors.forename: Oscar
authors.initials: O
authors.lastname: Hernández-Hernández
authors.affiliation: Inserm U781; Hôpital Necker Enfants Malades; Paris, France ; Université Paris Descartes-Sorbonne Paris Cité; Institut Imagine; Paris, France.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Sicot
authors.affiliation: Inserm U781; Hôpital Necker Enfants Malades; Paris, France ; Université Paris Descartes-Sorbonne Paris Cité; Institut Imagine; Paris, France.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Dinca
authors.affiliation: Inserm U781; Hôpital Necker Enfants Malades; Paris, France ; Université Paris Descartes-Sorbonne Paris Cité; Institut Imagine; Paris, France.
authors.forename: Aline
authors.initials: A
authors.lastname: Huguet
authors.affiliation: Inserm U781; Hôpital Necker Enfants Malades; Paris, France ; Université Paris Descartes-Sorbonne Paris Cité; Institut Imagine; Paris, France.
authors.forename: Annie
authors.initials: A
authors.lastname: Nicole
authors.affiliation: Inserm U837-1; Alzheimer and Tauopathies; Université Lille Nord de France; Centre Jean Pierre Aubert; Lille, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Buée
authors.affiliation: Inserm U781; Hôpital Necker Enfants Malades; Paris, France ; Université Paris Descartes-Sorbonne Paris Cité; Institut Imagine; Paris, France.
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.affiliation: Inserm U837-1; Alzheimer and Tauopathies; Université Lille Nord de France; Centre Jean Pierre Aubert; Lille, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sergeant
authors.affiliation: Inserm U781; Hôpital Necker Enfants Malades; Paris, France ; Université Paris Descartes-Sorbonne Paris Cité; Institut Imagine; Paris, France.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Gourdon
authors.affiliation: Inserm U781; Hôpital Necker Enfants Malades; Paris, France ; Université Paris Descartes-Sorbonne Paris Cité; Institut Imagine; Paris, France.
authors.forename: Mário
authors.initials: M
authors.lastname: Gomes-Pereira
keywords: RAB3A; RNA splicing; RNA toxicity; central nervous system; myotonic dystrophy type 1; synapsin I; synaptic function; synaptic protein; transgenic mice; trinucleotide repeat expansion