Molecular etiology of early onset dystonia

 描述(由申请人提供)：(总体摘要)肌张力障碍是第三种最常见的运动障碍，大多数病例具有遗传倾向。我们的总体目标是阐明早发性遗传性疾病的分子、细胞和神经元回路缺陷。 并寻找其病因的共同途径和潜在的靶向药物进行治疗干预。我们团队的成员发现了三个导致早发性肌张力障碍的基因，TOR1A(DYT1)、THAP1(DYT6)和GNAL(DYT25)，并建立并鉴定了DYT1肌张力障碍的小鼠和果蝇模型，并启动了对DYT6和DYT25肌张力障碍小鼠模型的研究。我们假设，其核心病理生理学在于神经递质信号的异常，主要是在纹状体，它在整个生命过程中表现为异常的突触可塑性。研究将分析这些肌张力障碍小鼠模型中的神经元培养和神经生理学，以及果蝇突变体中的增强/抑制基因。常见的主题包括纹状体中胆碱能和多巴胺能神经递质的相互作用，信号蛋白的转录和功能控制，以及核糖核蛋白颗粒(RNPs)中mRNAs的运输以便在突触处翻译。我们将通过一系列研究工具来探讨这些主题，包括最先进的人类分子遗传学，原代神经元和iPS细胞来源的神经元培养，以及使用遗传和细胞生物学方法检查的果蝇和小鼠肌张力障碍模型，以及小鼠模型中切片和微透析的电生理学分析。这项高度集成的P01将由主任Xandra Breakefield博士和联席主任Laurie Ozelius领导，包括：项目1--“原发性扭转肌张力障碍的基因和易感因素”(PI)。西奈半岛。项目2--“TorsinA作为受体介导的信号传递中的关键环节”(Pi Xandra Breakefield博士，共同是D.Cristopher Bragg博士和Naoto Ito博士，马萨诸塞州。项目3--“肌张力障碍小鼠模型中的胆碱能和多巴胺能机制”(大卫·斯坦德尔特博士，大学。艾拉。核心A-管理；核心B-临床核心(马萨诸塞州Nutan Sharma博士总医院)。临床信息和样本直接输入项目1、2和3。这些研究将阐明与人类肌张力障碍有关的常见分子途径，以指导治疗进展。

 DESCRIPTION (provided by applicant): (Overall Abstract) Dystonia is the third most common movement disorder with most cases having a hereditary predisposition. Our overall goal is to elucidate the molecular, cellular and neuronal circuitry defects in hereditary forms of early onset dystonia and to find common pathways in their etiology and potential targeted drugs for therapeutic intervention. Members of our team discovered three genes underlying early onset dystonia, TOR1A (DYT1), THAP1 (DYT6) and GNAL (DYT25) and have developed and characterized mouse and Drosophila models of DYT1 dystonia, as well as initiating studies on mouse models of DYT6 and DYT25 dystonia. We hypothesize that the core pathophysiology lies in abnormal neurotransmitter signaling, primarily in the striatum, which manifests throughout life as abnormal synaptic plasticity. Studies will analyze neuronal cultures, as well as neurophysiology in these dystonia mouse models, as well as enhancer/suppressor genes in Drosophila mutants. Common themes include cholinergic and dopaminergic neurotransmitter interactions in the striatum, transcriptional and functional control of signaling proteins, and transport of mRNAs in ribonucleoprotein particles (RNPs) for translation at synapses. We will approach these themes with an armamentarium of research tools, including state-of-the-art human molecular genetics, primary neuronal and iPS cell-derived neuronal cultures, and Drosophila and mouse models of dystonia examined using genetic and cell biologic methods and electrophysiologic analysis of slice explants and microdialysis in mouse models. This highly integrated P01 will be led by Dr. Xandra Breakefield, Director and Laurie Ozelius, Co-Director and includes: Project 1 - "Genes and susceptibility factors in primary torsion dystonia" (PI Dr. Laurie Ozelius, Mt. Sinai Sch. Med.); Project 2 - "TorsinA as a key link in receptor-mediated signaling" (PI Dr. Xandra Breakefield, Co-Is Drs. D. Cristopher Bragg and Naoto Ito, Mass. Gen. Hosp.); Project 3 - "Cholinergic and dopaminergic mechanisms in mouse models of dystonia" (Dr. David Standaert, Univ. Ala. Birmingham); Core A - Administration; and Core B - Clinical Core (Dr. Nutan Sharma, Mass. Gen. Hosp.). Clinical information and samples feed directly into Projects 1, 2 and 3. These studies will elucidate common molecular pathways involved in human dystonia to inform therapeutic advances.