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“运动障碍，其特征是持续或间歇性的肌肉收缩引起异常，通常重复，运动，姿势或两者兼而有之。可能是许多神经退行性的临床体征，并且神经代谢疾病。病因类别包括孤立的肌张力障碍，继发性肌张力障碍，肌张力障碍和肌张力障碍疾病。据信许多孤立的肌张力障碍病例在起源和GNAN中的突变可能是最普遍的已知遗传原因，主要是成人发作孤立的肌张力障碍。 Gnal编码Gα（OLF）[主要同工型]和XLGα（OLF）[长同工型] 用人纹状体和小脑表达。我们建议的总体目标是使用Gα（OLF）/XLGα（OLF）缺乏症状是了解孤立肌张力障碍的细胞病理生物学的桥梁，以及有条件的员工敲除（CKO）小鼠模型探索驱动孤立肌张力障碍的神经回路。这些目标将是通过三个特定目标实现。首先，我们将确定主要和长Gnal的中枢神经系统定位具有细胞类型特异性的同工型。其次，我们将表征表观遗传标记的暂时变化（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培养基中棘神经元（IMSN），直接途径MSN（DMSNS）和Purkinje细胞（PCS）。第三，我们将确定GNAL CKO在IMSN和PC中的行为效应。这些目标的完成将从我们目前对孤立和迟发性肌张力障碍发病机理和 Gα（OLF）/XLGα（OLF）信号通路。