Genetic Control of Purkinje Cell Degeneration

浦肯野细胞变性的遗传控制

• 批准号: 7387574
• 负责人: SUSAN L ACKERMAN
• 金额: $ 34.17万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 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/7387574
• 关键词: Adult; Affect; Alanine-Specific tRNA; Alanine-tRNA Ligase; Alleles; Alzheimer' s Disease; Amino Acids; Amyotrophic Lateral Sclerosis; Ankyrin Repeat; Ataxia; Axonal Transport; Brain region; CAST/Ei Mouse; Cell Death; Cell Nucleolus; Cell Nucleus; Cell physiology; Cells; Cerebellum; Cessation of life; Codon Nucleotides; Cytoplasm; Data; Defect; Degenerative Disorder; Degradation Pathway; Disease; Endoplasmic Reticulum; Functional disorder; Generations; Genes; Genetic; Grant; Human; Huntington Disease; Individual; Laboratories; Lesion; Mediating; Modeling; Molecular; Molecular Chaperones; Motor; Movement; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Parkinson Disease; Pathogenesis; Phenotype; Point Mutation; Population Heterogeneity; Proteins; Public Health; Purkinje Cells; Relative (related person); Research; Role; Specificity; Stress; Synapses; System; Testing; Transducers; Transfer RNA; Ubiquitin; aging population; familial Alzheimer disease; in vivo; loss of function; loss of function mutation; mind control; multicatalytic endopeptidase complex; mutant; neuron loss; novel; novel therapeutics; null mutation; polyglutamine; prevent; protein degradation; protein misfolding; research study; response; therapeutic target

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）：在许多遗传性和散发性神经变性形式中观察到错误折叠蛋白，并且与多种神经元紊乱相关。在某些家族性疾病中，疾病相关蛋白的错误折叠是由于编码该蛋白的基因内的突变造成的。然而，其他神经退行性疾病中蛋白质错误折叠的机制，特别是这些疾病的散发性、迟发性形式，仍然很大程度上未知。我们的表型驱动方法已经发现了新的功能丧失突变，这些突变会导致蛋白质错误折叠和神经变性。特别是，我们已经证明编码丙氨酰 tRNA 合成酶 (AlaRS) 的基因中的编辑突变会导致 tRNA 错误充电和浦肯野细胞中错误折叠蛋白的积累。重要的是，我们的实验室还使用正向遗传方法，发现了一种新基因 Stim，该基因可以细胞自主地抑制这些神经元中蛋白质错误折叠的积累及其随后的退化。该提案描述了通过产生 AlaRS 编辑缺陷更严重的小鼠来测试浦肯野细胞以外的神经元对错误翻译的敏感性的实验。 Stim 在其他神经元中的功能将在该模型中进行测试。我们还将通过调节泛素/蛋白酶体系统来确定 Stim 在清除错误折叠蛋白质中的作用。最后，将在该基因有条件无效突变的小鼠中评估 Stim 功能完全丧失的影响。 拟议研究与公共健康的相关性：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，包括帕金森病、阿尔茨海默病、亨廷顿病和肌萎缩侧索硬化症。该提案中概述的实验将进一步定义一种新基因，该基因可抑制神经元死亡以及伴随的运动异常，这些运动异常是由于小脑（控制运动协调的大脑区域）浦肯野神经元中异常蛋白质的积累而发生的。此外，还将测试该基因抑制大脑其他区域神经元功能障碍的能力。这些实验的结果可能为神经元退行性疾病提供新的治疗靶点。