Pathobiology of GNAL-Associated Dystonia

GNAL 相关肌张力障碍的病理学

基本信息

批准号：
10453157
负责人：
MARK S LEDOUX
金额：
$ 17.94万
依托单位：
UNIVERSITY OF MEMPHIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-15 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10453157
关键词：
ADORA2A gene Acute Address Adenylate Cyclase Adult Affect Animal Model Antipsychotic Agents Autopsy Behavioral Biological Models CHEK1 gene Catalepsy Categories Cell Cycle Regulation Cell Death Cell model Cerebellum Chromatin Structure Chronic Clinical Collection Corpus striatum structure Coupled Cyclic AMP DNA DNA Double Strand Break DNA Methylation DNA Repair DNA Repair Pathway DNA Structure DNA lesion Data Defect Development Disease Disorder of neurometabolic regulation Dopamine D1 Receptor Dopamine D2 Receptor Double Strand Break Repair Dysmorphology Dystonia Dystonia 4 Epigenetic Process Etiology Euchromatin Exhibits Family member Functional disorder G1/S Checkpoint Pathway Gene Expression Genes Genetic Genetic Transcription Goals Haloperidol Heterochromatin Heterotrimeric GTP-Binding Proteins Histone H3 Human Inherited Spinocerebellar Degenerations Intervention Knockout Mice Link Mediating Mitotic Molecular Motor Movement Movement Disorders Mus Muscle Contraction Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Operative Surgical Procedures Pathogenesis Pathologic Pathway interactions Pattern Pharmacology Phosphorylation Play Posture Protein Isoforms Purkinje Cells Research Reverse Transcriptase Polymerase Chain Reaction Role SETX gene Secondary Dystonia Signal Pathway Site Somatic Mutation Specificity Structural defect Syndrome TOR1A gene Variant Work aged arm cell type chromatin modification chromatin remodeling conditional knockout epigenetic silencing histone modification loss of function loss of function mutation middle age mouse model neural circuit proband protein complex receptor response

项目摘要

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.

肌张力障碍最近被重新定义为“以持续或间歇性运动为特征的运动障碍” 肌肉收缩导致异常的、经常重复的运动、姿势或两者兼而有之。” 临床症状可能是许多神经退行性疾病和神经退行性疾病的表现或突出表现神经代谢障碍的病因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有肌张力障碍和肌张力障碍，据信许多病例都是孤立性肌张力障碍。 GNAL 的起源和突变可能是最常见的已知遗传原因，主要是成人 GNAL 编码 Gα(olf) [主要亚型] 和 XLGα(olf) [长亚型]。我们建议的总体目标是使用 Gα(olf)/XLGα(olf)。缺陷作为了解孤立性肌张力障碍的细胞病理学的桥梁，并采用有条件的敲除（cKO）小鼠模型来探索驱动孤立性肌张力障碍的神经回路。首先，我们将确定主要和长Gnal的CNS定位。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) 缺陷相关的基因表达间接通路中型多棘神经元 (iMSN)、直接通路 MSN (dMSN) 和浦肯野细胞 (PC)。第三，我们将确定 Gnal cKO 在 iMSN 和 PC 中的行为效果完成这些目标将。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。