A Novel Ubiquitin-Dependent Pathogenic Pathway in Spongiform Neurodegeneration

海绵状神经变性中新的泛素依赖性致病途径

• 批准号: 7696228
• 负责人: Lih-Shen Chin
• 金额: $ 31.78万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7696228
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Age of Onset; Alzheimer' s Disease; Astrocytosis; Autophagocytosis; Biochemical; Biological; Biological Assay; Biological Process; Brain; Carrier Proteins; Cell Surface Receptors; Cell physiology; Cells; Complex; Creutzfeldt-Jakob Syndrome; Development; Diffuse; Endosomes; Event; Fingers; Functional disorder; Genes; Genetic; Goals; Health; Human; Inherited; Lewy Bodies; Lewy Body Disease; Link; Lysosomes; Mediating; Mitochondria; Molecular; Molecular Genetics; Mus; Mutant Strains Mice; Nerve Degeneration; Nerve Tissue; Neurodegenerative Disorders; Neurons; Oxidative Stress; Pathology; Pathway interactions; Patients; Peptide Hydrolases; Play; Prion Diseases; Prions; Process; Proteins; Regulation; Reporting; Research; Resistance; Role; Signal Pathway; Signal Transduction; Site; Sorting - Cell Movement; TSG101 gene; Testing; Therapeutic; Ubiquitin; Ubiquitination; age related; combat; follow-up; insight; loss of function; mahogunin protein; multicatalytic endopeptidase complex; mutant; neuron loss; neuronal survival; novel; novel therapeutics; null mutation; protein aggregate; public health relevance; research study; trafficking; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Spongiform neurodegeneration is a unique form of neurodegeneration characterized by vacuolation in neurons, neuronal cell death, and astrocytosis. Spongiform neurodegeneration is best known as the hallmark of prion disease, and this pathology is also present in the brains of patients suffering from Alzheimer's disease, diffuse Lewy body disease, and acquired immune deficiency syndrome (AIDS). The most common human prion disease is Creutzfeldt-Jakob disease (CJD), which occurs in sporadic, infectious, and inherited forms. The sporadic CJD form accounts for 85% of cases and is a late-onset (average age of onset = 60 years) neurodegenerative disorder of unknown cause. Although the prion protein has been extensively studied, the pathogenic mechanism underlying spongiform neurodegeneration remains elusive. Interestingly, a recent genetic study reveals that a null mutation in the gene encoding a novel protein called Mahogunin (Mgrn1) causes age-dependent, progressive spongiform neurodegeneration in mice that includes many features of prion disease but without accumulation of protease-resistant prion protein. At present, very little is known about the biological function of Mgrn1 and how loss of Mgrn1 function causes spongiform neurodegeneration. Mgrn1 contains a RING finger, a motif thought to be the key determinant of E3 ubiquitin-protein ligase activity. It has been speculated that loss of Mgrn1 function may cause spongiform neurodegeneration by impairing the ubiquitination and subsequent proteasomal degradation of yet-to-be-identified substrate(s) of Mgrn1. In contrast, the applicant's preliminary results have led to an intriguing hypothesis that Mgrn1 functions in a proteasome-independent, ubiquitin signalling pathway and suggest a novel mechanism by which defective ubiquitination may cause spongiform neurodegeneration. In this project, the applicant's group will follow up on these exciting results and use a combination of biochemical, cell biological, and molecular genetic approaches to investigate the cellular role of Mgrn1 E3 ligase, identify its substrates, and elucidate the molecular mechanism by which loss of Mgrn1 function causes age-dependent spongiform neurodegeneration. Completion of the proposed project should advance our understanding of the pathogenic mechanism underlying spongiform neurodegeneration and facilitate the development of new therapeutic strategies for treating age-related neurodegenerative disorders. PUBLIC HEALTH RELEVANCE: Spongiform neurodegeneration is most commonly associated with prion disease, but also occurs in patients suffering from age-related neurodegenerative disorders, such as Alzheimer's disease and diffuse Lewy body disease. The goal of the proposed research is to define the molecular pathogenic mechanism that causes age-dependent spongiform neurodegeneration. The results of the proposed studies will provide fundamental information needed for the development of effective therapeutics to combat age-related neurodegenerative diseases.

描述（由申请人提供）：海绵状神经变性是一种独特的神经变性形式，其特征是神经元，神经元细胞死亡和星形细胞增多症的液泡。海绵状神经退行性变性是最著名的，是prion病的标志，这种病理学也存在于患有阿尔茨海默氏病，弥漫性路易疾病和获得免疫缺陷综合征（AIDS）的患者的大脑中。最常见的人类prion病是Creutzfeldt-Jakob病（CJD），它发生在零星，传染性和遗传形式中。零星的CJD形式占病例的85％，是未知原因的神经退行性疾病的晚期（平均发病年龄= 60岁）。尽管对prion蛋白进行了广泛的研究，但海绵状神经变性的基础致病机制仍然难以捉摸。有趣的是，最近的一项遗传研究表明，编码一种新型蛋白质（MGRN1）的基因中的无效突变会导致小鼠的年龄依赖性，进行性的海绵神经变性，其中包括许多prion疾病的特征，但没有蛋白酶抗性的prion蛋白蛋白。目前，关于MGRN1的生物学功能以及MGRN1功能的丧失如何引起海绵神经变性。 MGRN1包含一个环手指，这是一个被认为是E3泛素 - 蛋白蛋白连接酶活性的关键决定因素。据推测，MGRN1功能的丧失可能通过损害MGRN1的尚未识别的底物的泛素化和随后的蛋白酶体降解来引起海绵神经退行性。相比之下，申请人的初步结果导致了一个有趣的假设，即MGRN1在蛋白酶体独立于泛素信号传导途径中起作用，并提出了一种新的机制，通过这种新机制，泛素化可能会导致海绵神经变性。在该项目中，申请人组将跟进这些令人兴奋的结果，并结合生化，细胞生物学和分子遗传方法来研究MGRN1 E3连接酶的细胞作用，识别其底物，并阐明其底物，并阐明MGRN1功能的分子机制，从而导致年龄依赖性的Spongoge Spongoge Spongondemagons spognsiforper spongodiform spongodiformerodegodegeneration。拟议项目的完成应提高我们对海绵神经退行性基础的致病机制的理解，并促进开发用于治疗与年龄相关的神经退行性疾病的新治疗策略。公共卫生相关性：海绵状神经变性最常见于病毒疾病，但也发生在患有与年龄相关的神经退行性疾病的患者中，例如阿尔茨海默氏病和弥漫性路易斯·里维体内疾病。拟议的研究的目的是定义导致年龄依赖性海绵神经变性的分子致病机制。拟议研究的结果将为开发有效的治疗剂来打击与年龄相关的神经退行性疾病所需的基本信息。