Cerebellar Dysfunction in DYT1

DYT1 中的小脑功能障碍

基本信息

批准号：
10297853
负责人：
Kamran Khodakhah
金额：
$ 46.03万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10297853
关键词：
Acute Address Adolescent Adult Age Agonist Agreement Amino Acids Animal Model Animals Area Basal Ganglia Brain Brain region Cerebellar Cortex Cerebellar Diseases Cerebellar Nuclei Cerebellum Deep Brain Stimulation Development Disease Dystonia Embryo Embryonic Development Engineering Exhibits Financial compensation Focal Dystonias Functional disorder Genetic Models Goals Human Inherited Intervention Knock-out Modeling Molecular Movement Movement Disorders Mus Muscle Mutation Neurologic Neurons Output Parkinson Disease Pathway interactions Patients Pattern Pharmacology Posture Purkinje Cells Research Rodent Rodent Model Symptoms Testing Thalamic structure Therapeutic Therapeutic Intervention TorsinA Transgenic Mice Tremor Work antagonist base disability early onset generalized torsion dystonia knock-down loss of function loss of function mutation motor symptom mouse model new therapeutic target postnatal protein expression protein function relating to nervous system small hairpin RNA therapeutic target therapeutically effective

项目摘要

Abstract DYT1 is a debilitating movement disorder caused by loss-of-function mutations in torsinA. How these mutations cause dystonia remains unknown. Mouse models which have embryonically targeted torsinA have failed to recapitulate the dystonia seen in patients, possibly due to differential developmental compensation between rodents and humans. To address this issue, we have developed a new mouse model where torsinA is acutely knocked down in select brain regions of adult mice using shRNAs. We have found that torsinA knockdown in the cerebellum, but not in the basal ganglia, is sufficient to induce dystonia. Abnormal motor symptoms in dystonic animals were associated with irregular cerebellar output caused by changes in the intrinsic activity of both Purkinje cells and neurons of the deep cerebellar nuclei. This proposal capitalizes on this dystonic model of DYT1 to explore at circuit, neuronal, and molecular levels how loss of torsinA causes dystonia. The proposal is based on three specific aims. In the first specific aim we will test the hypothesis that in DYT1 abnormal cerebellar output causes dystonia by altering the activity of the basal ganglia via the thalamic disynaptic Cb-BG pathway that we have characterized. Specific Aim 2 will test the hypothesis that selective knock down of torsinA in cerebellar Purkinje cells and/or DCN neurons causes cerebellar dysfunction and dystonia. And lastly the third specific Aim tests the hypothesis that knock down of torsinA alters the intrinsic pacemaking of Purkinje cells and DCN neurons by altering the expression or function of select conductances. Successful accomplishment of the aims set will significantly advance our understanding of DYT1 dystonia, and may provide valuable potential therapeutic targets for its treatment.

抽象的 Dyt1是由Torsina的功能丧失突变引起的一种使人衰弱的运动障碍。这些如何突变导致肌张力障碍仍然未知。具有胚胎靶向Torsina的小鼠模型未能概括患者的肌张力障碍，可能是由于发育差异引起的啮齿动物和人类之间的补偿。为了解决这个问题，我们已经开发了一只新鼠标模型在成年小鼠的精选大脑区域中急性撞倒Torsina。我们已经发现小脑中的塔西娜（Torsina 肌张力障碍。肌张力动物的运动症状异常与小脑不规则相关由Purkinje细胞和深处神经元的内在活性变化引起的输出小脑核。该提议大写了Dyt1的这种肌张力模型，以在神经元中探索，和分子水平的躯干损失如何导致肌张力障碍。该提案基于三个具体目标。在第一个具体目的中，我们将检验以下假设。 dyt1异常小脑输出通过改变基底神经节的活性来引起肌张力障碍我们已经表征的丘脑disnnnnaptic CB-BG途径。具体目标2将检验假设在小脑Purkinje细胞和/或DCN神经元中的Torsina的选择性敲低会导致小脑功能障碍和肌张力障碍。最后，第三个特定目的检验了以下假设 Torsina通过改变表达或选择电导的功能。成功完成目标集将大大提高我们对Dyt1的理解肌张力障碍，可能为其治疗提供宝贵的潜在治疗靶标。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Acute cerebellar knockdown of Sgce reproduces salient features of myoclonus-dystonia (DYT11) in mice.

Sgce 的急性小脑抑制再现了小鼠肌阵挛肌张力障碍 (DYT11) 的显着特征。

DOI：
10.7554/elife.52101
发表时间：
2019
期刊：
eLife
影响因子：
7.7
作者：
Washburn,Samantha;Fremont,Rachel;Moreno-Escobar,MariaCamila;Angueyra,Chantal;Khodakhah,Kamran
通讯作者：
Khodakhah,Kamran