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Characterization of the involvement of the cerebellum in animal models of C9orf72 ALS/FTD

C9orf72 ALS/FTD 动物模型中小脑参与的表征

基本信息

批准号：
10041549
负责人：
YUQING LI
金额：
$ 41.94万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10041549
关键词：
Acute Affect Age-Months Amyotrophic Lateral Sclerosis Anatomy Animal Disease Models Animal Model Antisense RNA Autopsy Bacterial Artificial Chromosomes Behavior Behavioral Biochemical Biochemistry Brain C9ORF72 Calcium Caregivers Cells Cerebellar Diseases Cerebellar degeneration Cerebellum Cognitive deficits Data Dementia Dipeptides Disease Economic Burden Electrophysiology (science)Environment Equilibrium Feedback Frontotemporal Dementia Functional disorder Funding Genes Genetic Goals Individual Introns Ion Channel Knockout Mice Knowledge Language Length Mediating Membrane Messenger RNA Molecular Genetics Morphology Motor Motor Neurons Motor output Mus Musculoskeletal Equilibrium Mutant Strains Mice Neurodegenerative Disorders Neurological Models Neurons Other Genetics Outcomes Research Pathogenesis Pathologic Pathology Report Patients Persons Phenotype Play Potassium Potassium Channel Property Proteins Purkinje Cells RNA Reporting Research Research Personnel Resources Role Spinal Cord Symptoms Techniques Temporal Lobe Testing Transcript Transgenic Mice Translations United States National Institutes of Health Walking Western Blotting Work behavior test behavioral variant frontotemporal dementia cognitive function early onset effective therapy emotional functioning frontal lobe frontotemporal lobar dementia-amyotrophic lateral sclerosis gain of function gray matter imaging study interdisciplinary approach loss of function motor deficit motor learning mouse model nervous system disorder protein TDP-43 therapeutic target

项目摘要

Project Summary: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive loss of motor neurons in the brain and spinal cord. Frontotemporal dementia (FTD) is early-onset dementia caused by degeneration of the frontal and temporal lobes with cognitive deficits and behavioral and language abnormalities. FTD shares pathophysiological features with ALS. A hexanucleotide repeat expansion in an intron of C9orf72 is the most frequently reported genetic cause of both diseases. Most of the pathophysiological studies of C9orf72 ALS/FTD and other types of ALS so far have been focused on upper and lower motor neurons. Recently, several functional studies have detected lower gray matter volume in the cerebellum in pre-symptomatic C9orf72 repeat expansion carriers, and anatomical evidence in C9orf72 disease mouse models have demonstrated cerebellar degeneration. Furthermore, pathology reports using postmortem or patient cells have demonstrated inclusions, RNA foci, dipeptide repeat proteins, and decreased C9orf72 mRNA and protein levels in the cerebellum, especially Purkinje cells, implicating cerebellar dysfunction in the pathogenesis of C9orf72 ALS/FTD. However, there are very few studies in animal disease models focusing on the cerebellum. Our strong preliminary data on C9orf72 knockout mice has revealed motor deficits and altered Purkinje cell activity. The functional significance of the cerebellum in the C9orf72 ALS/FTD pathogenesis is not known, let alone the detailed mechanisms. These unknowns hamper efforts to understand the pathophysiology of C9orf72 ALS/FTD and to develop effective therapies for patients. The overall goal of our research is to use transgenic mice to study the pathophysiology of C9orf72 ALS/FTD. The specific goal of this application is to characterize mouse models of C9orf72 ALS/FTD to determine the role of cerebellum in the pathogenesis of ALS and FTD. We hypothesize that at the presymptomatic stage, the C9orf72 mutant mice have motor deficits in coordination and balance, anatomical and functional deficits in the cerebellum, especially in the Purkinje cells due to the loss of function of C9orf72 protein and changes in the ion channels. We plan to test our hypothesis with the following Specific Aims: (1) we will examine C9orf72 mutant mice in the behavioral test battery, (2) we will characterize neuronal morphology, passive membrane properties, and intrinsic excitabilities of Purkinje cells, and (3) we will perform acutely dissociated Purkinje cell recording and Western blot analysis to determine ion channels involved in the altered firing of Purkinje cells. The successful completion of the Aims will expand the current knowledge concerning the involvement of the cerebellum in C9orf72-mediated ALS/FTD. This should significantly increase our understanding of the pathophysiology of C9orf72 ALS/FTD and contribute to the pathophysiological studies of other genetic ALS. Furthermore, the outcome of the research will support cerebellum as a potential therapeutic target to treat C9orf72 ALS/FTD. .

项目总结：肌萎缩侧索硬化症(ALS)是一种以进行性丢失为特征的神经退行性疾病大脑和脊髓中的运动神经元。额颞性痴呆(FTD)是由早发性痴呆引起的由于额叶和颞叶的退化，有认知缺陷以及行为和语言异常现象。FTD与ALS具有共同的病理生理特征。一种六核苷酸重复序列的扩增 C9orf72内含子是这两种疾病最常见的遗传原因。大多数到目前为止，C9orf72 ALS/FTD和其他类型的ALS的病理生理学研究主要集中在上部和较低的运动神经元。最近，一些功能研究发现大脑灰质体积较小。症状前C9orf72重复扩张型携带者的小脑和C9orf72的解剖学证据疾病小鼠模型已经显示出小脑变性。此外，病理报告使用死后或病人的细胞有包涵体、rna焦点、二肽重复蛋白，并减少。 C9ORF72在小脑，特别是浦肯野细胞中的mRNA和蛋白水平，与小脑有关 C9orf72 ALS/FTD发病机制障碍然而，关于动物疾病的研究很少。专注于小脑的模特。我们对C9orf72基因敲除小鼠的强有力的初步数据揭示了运动浦肯野细胞活动的缺陷和改变。C9orf72 ALS/FTD患者小脑的功能意义发病机制尚不清楚，更不用说详细的机制了。这些未知因素阻碍了人们理解目的：研究C9orf72 ALS/FTD的病理生理机制，并为患者开发有效的治疗方法。的总目标是本研究旨在利用转基因小鼠研究C9orf72 ALS/FTD的病理生理机制。的具体目标本应用是为了表征C9orf72 ALS/FTD小鼠模型，以确定小脑在 ALS和FTD的发病机制。我们推测，在症状前阶段，C9orf72突变小鼠有协调和平衡方面的运动缺陷，小脑的解剖和功能缺陷，尤其是在Purkinje细胞中，由于C9orf72蛋白功能的丧失和离子通道的改变。我们计划通过以下具体目标来验证我们的假设：(1)我们将检测C9orf72突变小鼠行为测试组合，(2)我们将表征神经元的形态、被动膜的性质，以及浦肯野细胞的内在兴奋性，以及(3)我们将进行急性分离的浦肯野细胞记录和蛋白质印迹分析以确定参与浦肯野细胞放电改变的离子通道。成功者 AIMS的完成将扩大目前关于小脑参与脑电活动的知识。 C9ORF72介导的ALS/FTD。这应该会大大增加我们对糖尿病的病理生理学的了解。 C9ORF72 ALS/FTD，为其他遗传性ALS的病理生理学研究做出了贡献。此外，研究结果将支持小脑作为治疗C9orf72 ALS/FTD的潜在治疗靶点。。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Review of the role of the endogenous opioid and melanocortin systems in the restless legs syndrome.

DOI：
10.1093/brain/awad283
发表时间：
2024-01-04
期刊：
Brain : a journal of neurology
影响因子：
0
作者：
通讯作者：

Alteration of the cholinergic system and motor deficits in cholinergic neuron-specific Dyt1 knockout mice.

DOI：
10.1016/j.nbd.2021.105342
发表时间：
2021-07
期刊：
Neurobiology of disease
影响因子：
6.1
作者：
Liu Y;Xing H;Sheng W;Singh KN;Korkmaz AG;Comeau C;Anika M;Ernst A;Yokoi F;Vaillancourt DE;Frazier CJ;Li Y
通讯作者：
Li Y

Deficiency of Meis1, a transcriptional regulator, in mice and worms: Neurochemical and behavioral characterizations with implications in the restless legs syndrome.