Transcriptional Signatures of Synaptic Vesicle Genes Define Myotonic Dystrophy Type I Neurodegeneration

Despite significant research, the biological mechanisms underlying the brain degeneration in Myotonic Dystrophy Type I (DM1) remain largely unknown. Here we have assessed brain degeneration by measuring the volume loss (VL) and cognitive deficits (CD) in two cohorts of DM1 patients, and associating them to the large-scale brain transcriptome maps provided by the Allen Human Brain Atlas (AHBA). From a list of preselected hypothesis-driven genes, three of them appear to play a major role in degeneration: dystrophin (DMD), alpha-synuclein (SNCA) and the microtubule-associated protein tau (MAPT). Moreover, a purely data-driven strategy identified gene clusters enriched for key biological processes in the central nervous system, such as synaptic vesicle recycling, localization, endocytosis and exocytosis, and the serotonin and dopamine neurotransmitter pathways. Therefore, by combining large-scale transcriptome interactions with brain imaging and cognitive function, we provide a new more comprehensive understanding of DM1 that might help define future therapeutic strategies and research into this condition.