Coupling of muscle blind-dependent RNA processing to the circadian clock in neuronal homeostasis and sleep

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Abstract: 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.