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

基本信息

批准号：
8512632
负责人：
Lih-Shen Chin
金额：
$ 28.57万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8512632
关键词：
Accounting Acquired Immunodeficiency Syndrome Age of Onset Alzheimer&apos 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 research study trafficking ubiquitin-protein ligase

项目摘要

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）：海绵状神经变性是神经变性的一种独特形式，其特征是神经元空泡化、神经元细胞死亡和星形细胞增多。海绵状神经变性是众所周知的朊病毒病的标志，这种病理学也存在于阿尔茨海默病、弥漫性路易体病和获得性免疫缺陷综合症（艾滋病）患者的大脑中。最常见的人类朊病毒病是克雅氏病 (CJD)，该病以散发性、传染性和遗传性形式发生。散发性克雅氏病占病例的 85%，是一种迟发性（平均发病年龄 = 60 岁）原因不明的神经退行性疾病。尽管朊病毒蛋白已被广泛研究，但海绵状神经变性的致病机制仍然难以捉摸。有趣的是，最近的一项基因研究表明，编码一种名为 Mahogunin (Mgrn1) 的新型蛋白质的基因的无效突变会导致小鼠出现年龄依赖性、进行性海绵状神经变性，其中包括朊病毒病的许多特征，但不积累蛋白酶抗性朊病毒蛋白。目前，人们对 Mgrn1 的生物学功能以及 Mgrn1 功能丧失如何导致海绵状神经变性知之甚少。 Mgrn1 包含一个环指，该基序被认为是 E3 泛素蛋白连接酶活性的关键决定因素。据推测，Mgrn1 功能的丧失可能会损害 Mgrn1 尚未鉴定的底物的泛素化和随后的蛋白酶体降解，从而导致海绵状神经变性。相比之下，申请人的初步结果得出了一个有趣的假设，即Mgrn1在不依赖于蛋白酶体的泛素信号通路中发挥作用，并提出了一种新的机制，通过该机制，缺陷性泛素化可能导致海绵状神经变性。在这个项目中，申请人的团队将跟进这些令人兴奋的结果，并结合使用生化、细胞生物学和分子遗传学方法来研究Mgrn1 E3连接酶的细胞作用，鉴定其底物，并阐明损失的分子机制。 Mgrn1 功能的丧失会导致年龄依赖性海绵状神经变性。该项目的完成将增进我们对海绵状神经变性致病机制的理解，并促进开发治疗与年龄相关的神经退行性疾病的新治疗策略。公共健康相关性：海绵状神经变性最常与朊病毒病相关，但也发生在患有与年龄相关的神经变性疾病（例如阿尔茨海默病和弥漫性路易体病）的患者中。拟议研究的目标是确定导致年龄依赖性海绵状神经变性的分子致病机制。拟议研究的结果将为开发有效疗法来对抗与年龄相关的神经退行性疾病提供所需的基本信息。