MECHANISMS OF RNA-MEDIATED CNS PATHOGENESIS IN MYOTONIC DYSTOPHY

RNA介导的强直性肌营养不良中枢神经系统发病机制

基本信息

批准号：
9105456
负责人：
MAURICE SCOTT SWANSON
金额：
$ 34.49万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-15 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9105456
关键词：
Address Adult Affect Alternative Splicing Amyotrophic Lateral Sclerosis Animal Model Binding Brain Candidate Disease Gene Central Nervous System Diseases Characteristics Congenital Disorders Development Disease Disease model Embryo Event Executive Dysfunction Failure Family Fragile X Syndrome Frontotemporal Dementia Functional disorder Future Generations Genes Genetic Transcription Hereditary Disease High-Throughput Nucleotide Sequencing Human Immunoprecipitation In Vitro Inherited Knock-out Knockout Mice Lesion Link Mediating Memory impairment Mental Retardation Microsatellite Repeats Modeling Molecular Muscular Dystrophies Myotonic Dystrophy Nervous System Physiology Neuraxis Neurologic Neuromuscular Diseases Neurons Outcome Pathogenesis Pathway interactions Pattern Phenotype Play Poly A Protein Isoforms Proteins REM Sleep RNA RNA Splicing Role Site Systemic disease Testing Tissues Transcript Translations Tremor/Ataxia Syndrome Untranslated Regions autistic behaviour base cerebral atrophy combinatorial crosslink crosslinking and immunoprecipitation sequencing disease mechanisms study fetal gamma-Aminobutyric Acid gene synthesis in vivo loss of function mouse model mutant novel sleep regulation spatial memory targeted treatment therapeutic target therapy development transcriptome transcriptome sequencing white matter

项目摘要

While myotonic dystrophy (DM) is classified as a muscular dystrophy, it is a progressive multi-systemic disease that has significant effects on central nervous system (CNS) function. These CNS manifestations include mental retardation and autistic behaviors in congenital DM and hypersomnia, executive dysfunction and cortical atrophy in the adult-onset form. Studies on the molecular basis of DM have revealed a novel disease mechanism, RNA-mediated pathogenesis, that involves the expansion of microsatellite C(C)TG repeats in two unrelated genes and the synthesis of toxic C(C)UG expansion RNAs. These pathogenic RNAs interfere with the normal alternative splicing functions of the CELF and MBNL proteins resulting in the persistence of, or reversion to, fetal isoforms in adult tissues. To determine if this RNA-mediated disease model is relevant to CNS dysfunction in DM, we have recently generated Mbnl2 knockout mice which recapitulate characteristic pathological features of the DM brain including abnormal REM sleep propensity and spatial memory deficits. In this proposal, we will first test the MBNL2 sequestration hypothesis for DM relevant CNS pathogenesis by demonstrating that transfer of MBNL2 from its normal RNA targets to C(C)UG repeats occurs in the DM brain. Next, we will determine if Mbnl2 knockout mice model the full range of DM CNS features and link specific mis-splicing events to characteristic disease manifestations. Finally, we will test the hypothesis that interactions between MBNL genes are disrupted in the congenital disease. These studies will provide novel animal models of adult-onset and congenital DM for future disease mechanism studies and the development of therapies that target the DM brain.

虽然肌营养不良（DM）被归类为肌肉营养不良，但它是一种进行性多系统性疾病，对中枢神经系统（CNS）功能具有重大影响。这些中枢神经系统的表现包括先天性DM和高血压，高管功能障碍和皮质萎缩的智力低下和自闭症行为。关于DM分子基础的研究表明，RNA介导的发病机理一种新型的疾病机制，涉及在两个无关基因中的微卫星C（C）TG重复序列的扩展以及毒性C（C）UG扩张RNA的合成。这些致病性RNA干扰了CELF和MBNL蛋白的正常替代剪接功能，从而导致成人组织中持续或恢复为胎儿同工型。为了确定这种RNA介导的疾病模型是否与DM中的CNS功能障碍有关，我们最近产生了MBNL2敲除小鼠，这些小鼠概括了DM脑的特征病理特征，包括异常的REM睡眠倾向和空间记忆缺陷。在此提案中，我们将首先通过证明MBNL2从其正常RNA靶标转移到C（C）UG重复序列的DM相关CNS发病机理的MBNL2隔离假设发生。接下来，我们将确定MBNL2基因敲除小鼠是否建模了DM CNS特征的全部范围，并将特定的错误分解事件与特征性疾病表现相关联。最后，我们将检验以下假设：先天性疾病中MBNL基因之间的相互作用受到破坏。这些研究将为未来的疾病机理研究以及针对DM脑的疗法的发展提供新的成人发作和先天性DM动物模型。