Excessive daytime sleepiness and other sleep perturbances are frequent and serious comorbidities in patients with myotonic dystrophy type 1 (DM1), a multi-system disease otherwise characterized by myotonia and cardiomyopathy. It is well-established that skeletal-muscle and cardiac phenotypes of DM1 are caused by dysregulation of muscle-specific splicing events due to sequestration of MBNL family RNA binding proteins (RBPs) by transcribed repeat RNAs; however, the molecular mechanisms underlying sleep disorders in DM1 are poorly understood. Loss of neuronal MBNL2 in mice recapitulates the CNS features of DM1 with no muscle or cardiac involvement and Mbnl2-/- mice display mis-timed sleep episodes and a loss of diurnal rhythmicity in RNA processing events, suggesting that disruption of circadian rhythm is central to DM1 pathobiology. I therefore propose that inhibition of MBNL proteins perturbs the core circadian timing mechanism leading to mis-allocation of sleep in DM1 and potentially contributing to central and peripheral disease phenotypes. To gain insight into interactions between MBNL and the circadian clock I have developed animal- and human iPSC-based models to define RNA processing events that alter molecular and behavioral circadian rhythms in DM1. My proposed studies will precisely determine the impact of MBNL inhibition by repeat RNA on the entrainment and maintenance of circadian rhythms within sleep-regulatory neurons and pinpoint specific MBNL-mediated RNA processing targets that disrupt the molecular clock and impair sleep in DM1. If successful these studies will define molecular pathways underlying sleep disorder in the context DM1-linked mutations and provide a springboard for the future development of disease models for therapeutic discovery in sleep biology.
Myotonic dystrophy (DM) is the most common form of muscular dystrophy affecting the adult population and is caused by mutations in repetitive DNA regions in the genome that spontaneously expand and cause muscle atrophy by sequestering and inhibiting the activity of RNA binding proteins. The most common non-muscular symptom in DM patients is a sleep disorder typically characterized by excessive daytime sleepiness (EDS), yet the molecular mechanisms linking repetitive DNA expansions to altered sleep are unknown. My proposed research aims to test the hypothesis that inhibition of the circadian clock underlies sleep disorders in DM1 and will provide insight into new signaling pathways that disrupt sleep and guide future efforts to better understand how sleep is regulated at the cellular level.
