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

摘要： 白天过度嗜睡和其他睡眠障碍是患者常见的严重并发症。 强直性肌营养不良1型(DM1)是一种多系统疾病，以肌强直和 心肌病。众所周知，DM1的骨骼肌和心脏表型是由 由于MBNL家族RNA结合蛋白的隔离而导致的肌肉特异性剪接事件的失调 (RBPs)；然而，DM1睡眠障碍的分子机制 人们对此了解甚少。小鼠神经元性MBNL2缺失重现无肌肉DM1的中枢神经系统特征 或心脏受累和Mbn12-/-小鼠表现出错误的睡眠发作和昼夜节律性丧失 RNA处理事件，表明昼夜节律的破坏是DM1病理生物学的中心。我 因此提出，抑制MBNL蛋白扰乱了核心的昼夜节律机制，导致 DM1中睡眠分配不当，并可能导致中枢和外周疾病的表型。至 深入了解MBNL与我开发的动物和人类生物钟之间的相互作用 基于IPSC的模型来定义改变分子和行为昼夜节律的RNA处理事件 DM1。我提出的研究将准确地确定重复RNA抑制MBNL对 睡眠调节神经元内昼夜节律的携带和维持 MBNL介导的RNA处理的目标是扰乱分子时钟并损害DM1的睡眠。如果 这些研究的成功将在DM1相关的背景下确定睡眠障碍的分子途径 突变并为未来开发用于治疗的疾病模型提供了跳板 睡眠生物学。

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.