Journal
RARE DISEASES
Volume 1, Issue 1, Pages -Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/rdis.25553
Keywords
myotonic dystrophy type 1; trinucleotide repeat expansion; RNA toxicity; RNA splicing; central nervous system; transgenic mice; synaptic function; synaptic protein; RAB3A; synapsin I
Categories
Funding
- ANR (Agence Nationale de Recherche, France)
- AFM (Association Francaise contre les Myopathies, France) [14687]
- INSERM (Institute National de la Sant et Recherche Medicale, France)
- Universite Paris Descartes (Paris, France)
- CONACyT (Consejo Nacional de Ciencia y Tecnologia, Mexico) [183697]
- Ministere Francais de la Recherche et Technologie
- AFM
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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 temporalregulated 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.
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