Abstract:
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Although traditionally regarded as a muscle disease, myotonic dystrophy type 1 (DM1) has emerged as a brain disorder. The congenital form of the disease presents severe mental retardation, whereas hypersomnia, learning problems, personality changes, social avoidance and anhedonia have been reported in adult and juvenile patients. DM1 is caused by the expansion of an unstable CTG trinucleotide repeat in the 3'UTR of the DMPK gene. Toxic CUG repeats accumulate in nuclear foci, affecting the levels and/or localisation of key splicing regulators and disrupting multiple downstream transcripts. It is still unclear to what extent RNA toxicity accounts for DM1 neurological manifestations, nor is it known which pathways are affected in the central nervous system (CNS). In order to investigate DM1 pathophysiology, we have used DMSXL mice expressing an expanded DMPK transgene (containing >1000 CTG) in multiple tissues. These animals recreate important aspects of the CTG repeat dynamics and disease phenotype, notably in brain. DMSXL brains show region-specific foci accumulation and critical splicing abnormalities, which are associated with abnormal localisation and steady-state levels of splicing regulators. Tau hyperphosphorylation in DMSXL brains resemble the tauopathy described in patients. In addition, DMSXL mice exhibit relevant behavioural phenotypes, such as novelty-induced inhibition, anhedonia and a tendency for reduced working memory and social interaction. Given their molecular and behavioural deficits, we have taken advantage of DMSXL mice to identify novel disease intermediates and pathways affected by the DM1 mutation in the CNS. A global proteomic approach revealed abnormal expression and post-translational modifications of proteins involved in vesicle transport, suggesting altered vesicle trafficking and synaptic transmission in response to expanded CTG repeats. To test this hypothesis we have measured vesicle release in cell culture, and found abnormal neurosecretion in neuronal cell lines transfected with expanded CTG repeats. It is our hypothesis that abnormal vesicle transport and neurotransmission may contribute to DM1 neurological symptoms. In conclusion, DMSXL mice provide an excellent tool to further dissect DM1 neuropathogenesis and to establish a mechanistic link between repeat expansion, dysfunctional pathways and the development of neurological manifestations. This study was supported by research grants from AFM, ANR and Inserm (France).
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