Of Mice and Men: Advances in the Understanding of Neuromuscular Aspects of Myotonic Dystrophy

Intensive effort has been directed toward the modeling of myotonic dystrophy (DM) in mice, in order to reproduce human disease and to provide useful tools to investigate molecular and cellular pathogenesis and test efficient therapies. Mouse models have contributed to dissect the multifaceted impact of the DM mutation in various tissues, cell types and in a pleiotropy of pathways, through the expression of toxic RNA transcripts. Changes in alternative splicing, transcription, translation, intracellular RNA localization, polyadenylation, miRNA metabolism and phosphorylation of disease intermediates have been described in different tissues. Some of these events have been directly associated with specific disease symptoms in the skeletal muscle and heart of mice, offering the molecular explanation for individual disease phenotypes. In the central nervous system (CNS), however, the situation is more complex. We still do not know how the molecular abnormalities described translate into CNS dysfunction, nor do we know if the correction of individualmolecular events will provide significant therapeutic benefits. The variability in model design and phenotypes described so far requires a thorough and critical analysis. In this review we discuss the recent contributions of mouse models to the understanding of neuromuscular aspects of disease, therapy development, and we provide a reflective assessment of our current limitations and pressing questions that remain unanswered.