Genetic Control of Purkinje Cell Degeneration

浦肯野细胞变性的遗传控制

基本信息

批准号：
7994787
负责人：
SUSAN L ACKERMAN
金额：
$ 33.57万
依托单位：
JACKSON LABORATORY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-30 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7994787
关键词：
Alanine-tRNA Ligase Alleles Alzheimer&apos s Disease Brain region Cells Cerebellum Cessation of life Degenerative Disorder Disease Environment Enzymes Funding Generations Genes Genetic Genets Grant Human Huntington Disease Knock-out Laboratories Manuscripts Modeling Motor Movement Mus Mutation Nature Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Paper Parkinson Disease Phenotype Point Mutation Principal Investigator Progress Reports Proteins Public Health Publications Published Comment Publishing Purkinje Cells Research Resources Role Study models System Testing Transfer RNA Ubiquitin cell type design embryonic stem cell gene function loss of function mutation mind control multicatalytic endopeptidase complex new therapeutic target novel null mutation programs protein misfolding research study response

Alanine-tRNA Ligase Alleles Alzheimer&apos s Disease Brain region Cells Cerebellum Cessation of life Degenerative Disorder Disease Environment Enzymes Funding Generations Genes Genetic Genets Grant Human Huntington Disease Knock-out Laboratories Manuscripts Modeling Motor Movement Mus Mutation Nature Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Neurons Paper Parkinson Disease Phenotype Point Mutation Principal Investigator Progress Reports Proteins Public Health Publications Published Comment Publishing Purkinje Cells Research Resources Role Study models System Testing Transfer RNA Ubiquitin cell type design embryonic stem cell gene function loss of function mutation mind control multicatalytic endopeptidase complex new therapeutic target novel null mutation programs protein misfolding research study response

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项目摘要

DESCRIPTION (provided by applicant): Misfolded proteins are observed in many genetic and sporadic forms of neurodegeneration and are associated with multiple neuronal disturbances. In some familial forms of disease, misfolding of the disease-related protein is due to mutations within the gene that encodes the protein. However, the mechanisms that underlie protein misfolding in other neurodegenerative diseases, in particular the sporadic, late-onset forms of these disorders, remain largely unknown. Our phenotype-driven approach has identified novel loss-of-function mutations that result in protein misfolding and neurodegeneration. In particular we have demonstrated that an editing mutation in the gene encoding alanyl tRNA synthetase (AlaRS) causes tRNA mischarging and accumulation of misfolded proteins in Purkinje cells. Importantly, also using a forward genetic approach, our laboratory has identified a novel gene, Stim, which cell-autonomously suppresses the accumulation of protein misfolding in these neurons and their subsequent degeneration. This proposal describes experiments to test the sensitivity of neurons, other than Purkinje cells, to mistranslation, via the generation of a mouse with a more severe deficiency in AlaRS editing. The function of Stim in other neurons will be tested in this model. We will also establish the role of Stim in the clearance of misfolded proteins via modulation of ubiquitin/proteasome system. Lastly, the effects of complete loss of Stim function will be assessed in mice with a conditional null mutation in this gene. Relevance of the proposed research to public health: The accumulation of abnormal proteins in neurons is associated with many human neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, Huntington's disease and ALS. The experiments outlined in this proposal will further define a novel gene that suppresses neuron death and the accompanying movement abnormalities that occur in response to the accumulation of abnormal proteins in Purkinje neurons in the cerebellum, the region of the brain that controls motor coordination. In addition, the ability of this gene to suppress neuronal dysfunction in other regions of the brain will be tested. The results from these experiments will potentially provide novel therapeutic targets for neuronal degenerative disorders.

描述（由申请人提供）：在许多遗传和零星形式的神经变性形式中观察到错误折叠的蛋白质，并与多种神经元障碍有关。在某些家族形式的疾病中，与疾病相关的蛋白质的错误折叠是由于编码蛋白质的基因中的突变所致。然而，在其他神经退行性疾病中脱eli的基础的机制，尤其是这些疾病的零星，晚期形式的机制，基本上是未知的。我们的表型驱动方法已经确定了新型功能丧失突变，从而导致蛋白质折叠和神经退行性变化。特别是我们已经证明，编码丙酰基TRNA合成酶（ALARS）的基因中的编辑突变会导致tRNA误导并积累错误的purkinje细胞中的蛋白质。重要的是，我们的实验室还采用了正向遗传学方法，确定了一种新型基因stim，该基因可以自主地抑制这些神经元中蛋白质折叠率误折的积累及其随后的变性。该建议描述了通过产生具有更严重的Alars编辑缺乏的小鼠来测试神经元（Purkinje细胞）敏感性的实验。在此模型中将测试刺激在其他神经元中的功能。我们还将通过调节泛素/蛋白酶体系统来确定刺激在清除错误折叠蛋白质中的作用。最后，将在该基因中有条件零突变的小鼠中评估完全丧失刺激功能的影响。拟议研究与公共卫生的相关性：神经元中异常蛋白质的积累与许多人类神经退行性疾病有关，包括帕金森氏病，阿尔茨海默氏病，亨廷顿氏病和ALS。该提案中概述的实验将进一步定义一个新的基因，该基因抑制神经元死亡和随之而来的运动异常，这些异常是响应于小脑中普林吉神经元异常蛋白质的积累而发生的，这是大脑控制运动配位的大脑区域。另外，将测试该基因抑制大脑其他区域中神经元功能障碍的能力。这些实验的结果可能会为神经元退行性疾病提供新的治疗靶标。