Pathobiology of GNAL-Associated Dystonia

肌张力障碍最近被重新定义为“以持续或间歇性 肌肉收缩导致不正常的，经常重复的，动作，姿势，或两者兼而有之。肌张力障碍也是一种 临床体征可能是许多神经退行性疾病的表现或突出表现， 神经代谢紊乱病因分类包括孤立性肌张力障碍，继发性肌张力障碍， 遗传性退行性疾病伴肌张力障碍和肌张力障碍+。许多孤立性肌张力障碍的病例被认为 GNAL中的突变可能是最普遍的已知遗传原因，主要是成人- 孤立性肌张力障碍GNAL编码Gα（olf）[主要亚型]和XLGα（olf）[长亚型]，两者都是 在人纹状体和小脑中表达。我们建议的总体目标是使用Gα（olf）/XLGα（olf） 缺乏作为理解孤立性肌张力障碍的细胞病理学的桥梁， 基因敲除（cKO）小鼠模型以探索驱动孤立性肌张力障碍的神经回路。这些目标将是 通过三个具体目标实现。首先，我们将确定中枢神经系统定位的主要和长期的Gnal 具有细胞类型特异性的同种型。其次，我们将描述表观遗传标记的时间变化 (DNA甲基化，组蛋白修饰）和与Gα（olf）/XLGα（olf）缺乏相关的基因表达。 间接途径中棘神经元（iMSN）、直接途径MSN（dMSN）和浦肯野细胞（PC）。 第三，我们将确定Gnal cKO在iMSN和PC中的行为影响。实现这些目标将 从根本上扩展了我们目前对孤立性和迟发性肌张力障碍发病机制的理解， Gα（olf）/XLGα（olf）信号通路。

Dystonia has recently been redefined as a “movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both.” Dystonia is also a clinical sign that can be the presenting or prominent manifestation of many neurodegenerative and neurometabolic disorders. Etiological categories include isolated dystonia, secondary dystonia, heredodegenerative diseases with dystonia, and dystonia plus. Many cases of isolated dystonia are believed to be genetic in origin and mutations in GNAL may be the most prevalent known genetic cause of mainly adult- onset isolated dystonia. GNAL encodes Gα(olf) [major isoform] and XLGα(olf) [long isoform] which are both expressed in human striatum and cerebellum. The overall goals of our proposal are to use Gα(olf)/XLGα(olf) deficiency as a bridge to understand the cellular pathobiology of isolated dystonia, and employ conditional knock-out (cKO) mouse models to explore the neural circuitry that drives isolated dystonia. These goals will be achieved through three specific aims. First, we will determine the CNS localization of the major and long Gnal isoforms with cell-type specificity. Second, we will characterize the temporal changes in epigenetic marks (DNA methylation, histone modifications) and gene expression associated with Gα(olf)/XLGα(olf) deficiency in indirect pathway medium spiny neurons (iMSNs), direct pathway MSNs (dMSNs), and Purkinje cells (PCs). Third, we will determine the behavioral effects of Gnal cKO in iMSNs and PCs. Completion of these aims will radically expand upon our current understanding of isolated and tardive dystonia pathogenesis and Gα(olf)/XLGα(olf) signaling pathways.