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.
Disclosure of Potential Conflicts of Interest
No potential conflict of interest was disclosed.
Acknowledgments
We are grateful to Amine Bouallague, the personnel of CERFE (Centre d’Exploration et de Recherche Fonctionelle Expérimentale, Genopole, Evry, France) and LEAT (Laboratoire d’Expérimentation Animale et de Transgénèse, Faculté de Médecine Paris Descartes) for attentively caring for the mice. We thank our colleagues at Inserm U781 and the DM1 French Splicing Network for helpful discussions. This work was supported by ANR (Agence Nationale de Recherche, France; project grant “DM1MICE”), AFM (Association Française contre les Myopathies, France; project grant number 14687), INSERM (Institute National de la Santé et Recherche Médicale, France) and Université Paris Descartes (Paris, France). O.H.H. was partially funded by a post-doctoral fellowship and research grant from CONACyT (Consejo Nacional de Ciencia y Tecnología, Mexico; grant number 183697). G.S. was awarded a PhD student fellowship from Ministère Français de la Recherche et Technologie and AFM.
Supplemental Material
Supplemental materials may be found here: www.landesbioscience.com/journals/rarediseases/article/25553
Notes
† These authors contributed equally to this work.