Parkin and MGRN1: common roles in mitochondria and neurodegeneration?

Parkin 和 MGRN1：在线粒体和神经退行性疾病中的共同作用？

• 批准号: 7878499
• 负责人: Teresa M Gunn
• 金额: $ 22.5万
• 依托单位: MC LAUGHLIN RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7878499
• 关键词: 1 year old; Affect; Age-Months; Alleles; Alzheimer' s Disease; Appearance; Biological Assay; Biological Markers; Brain; Calcium Signaling; Cell Culture System; Cell physiology; Cells; Complex; Defect; Disease; Family health status; Future; Genetic; Healthcare Systems; Human; Individual; Inherited; Laboratory Study; Mediating; Mitochondria; Mitochondrial Proteins; Molecular; Molecular Chaperones; Morphology; Mus; Mutant Strains Mice; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oxidative Stress; PARK2 gene; Parkinson Disease; Pathology; Phenotype; Predisposition; Proteins; Relative (related person); Respiration; Ring Finger Domain; Role; Societies; Sorting - Cell Movement; System; Testing; Ubiquitin; Ubiquitination; Vacuole; Work; early onset; mahogunin protein; mitochondrial dysfunction; multicatalytic endopeptidase complex; mutant; neuron loss; novel; novel strategies; parkin gene/protein; prevent; protein transport; public health relevance; therapeutic target; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): The molecular mechanisms that underlie common neurodegenerative diseases remain unclear, although studies have implicated mitochondrial dysfunction and ubiquitin-proteasome defects. The Gunn laboratory studies the RING-type E3 ubiquitin ligase Mahogunin Ring Finger-1 (MGRN1), loss of which causes progressive, widespread spongiform neurodegeneration in mice by 1 year of age. Mitochondrial dysfunction and elevated oxidative stress were detected in the brains of Mgrn1 null mutants by 1 month of age. Mutations in another RING-type E3, Parkin (PARK2), underlie ~50% of inherited and 10-15% of sporadic early-onset Parkinson's disease and cause mitochondrial dysfunction in mice. Recent studies implicate parkin in the autophagic clearance of damaged, depolarized mitochondria. Our preliminary studies indicate that 1) many MGRN1-interacting proteins also associate with parkin or show altered expression in the brains of parkin null mutant mice; 2) MGRN1 interacts with several mitochondrial proteins and colocalizes with mitochondria. We hypothesize that MGRN1 is a component of the mitochondrial chaperone system and that loss of MGRN1 function causes mitochondrial dysfunction that triggers parkin-mediated mitophagy. This hypothesis implies a direct connection between ubiquitination and mitochondrial function and represents a novel approach to considering their relationship to neurodegeneration. If MGRN1 has a direct role in mitochondria, future studies could test the effect of different mitochondrial-targeted therapies on the onset and progression of spongiform neurodegeneration in Mgrn1 null mutants and whether loss of MGRN1 function is a susceptibility factor for other neurodegenerative disorders. Aim 1: To test whether there is a genetic interaction between Mgrn1 and parkin. We will test the hypothesis that MGRN1 and parkin have overlapping functions by generating Mgrn1; parkin compound null mutant mice and performing histological and mitochondrial assays to determine whether loss of 1 or 2 functional Mgrn1 alleles alters the CNS phenotype of parkin null mutant mice, and vice versa. Aim 2: To examine whether parkin and MGRN1 have related mitochondrial functions. We will test the hypothesis that MGRN1 is a component of the mitochondrial chaperone system by examining the effect of disrupting MGRN1 on mitochondrial respiration and morphology and determining whether loss of MGRN1 function triggers parkin-mediated mitophagy. We will also examine whether MGRN1 interacts with, ubiquitinates and/or regulates the levels of specific mitochondrial proteins. PUBLIC HEALTH RELEVANCE: Neurodegenerative disorders have a significant impact on affected individuals, their families, the health care system, and society as a whole. They have many potential causes but even when a particular protein has been shown to cause neurodegeneration, exactly how it disrupts neuron function and survival is not well understood. The work outlined in this proposal will help us understand more about the function of a protein called Mahogunin Ring Finger-1 and whether it has similar function(s) in cells as parkin, which is disrupted in some people with inherited forms of Parkinson's disease. We hope that our work will help us understand how these diseases arise and, ultimately, how we can prevent or better treat them.

描述（由申请人提供）：基于常见神经退行性疾病的分子机制尚不清楚，尽管研究暗示了线粒体功能障碍和泛素 - 蛋白酶体缺陷。 Gunn实验室研究RING型E3泛素连接酶Mahogunin Ring Finger Finger-1（MGRN1），其损失会导致小鼠的渐进性，广泛的海绵神经变性，到1岁。到1个月大时，在MGRN1无效突变体的大脑中检测到线粒体功能障碍和氧化应激升高。另一个环类E3，Parkin（Park2）的突变，含有约50％的遗传性和10-15％的零星早期发作的帕金森氏病，并在小鼠中引起线粒体功能障碍。最近的研究暗示了帕金（Parkin）在受损的，去极化的线粒体的自噬清除中。我们的初步研究表明，1）许多MGRN1相互作用的蛋白也与帕金（Parkin）相关，或在parkin null突变小鼠的大脑中显示出改变的表达； 2）MGRN1与几种线粒体蛋白相互作用，并与线粒体共定位。我们假设MGRN1是线粒体伴侣系统的一个组成部分，而MGRN1功能的丧失会导致线粒体功能障碍，从而触发Parkin介导的线粒体。该假设意味着泛素化和线粒体功能之间的直接联系，并代表了一种考虑它们与神经变性关系的新方法。如果MGRN1在线粒体中具有直接作用，未来的研究可以测试不同线粒体靶向疗法对MGRN1 NULL突变体中海绵神经变性的发作和进展的影响，MMGRN1功能的丧失是否是其他神经变性疾病的易感因子。目标1：测试MGRN1和Parkin之间是否存在遗传相互作用。我们将检验以下假设：MGRN1和Parkin通过产生MGRN1具有重叠的功能； Parkin化合物无效突变小鼠并进行组织学和线粒体测定，以确定1或2个功能性MGRN1等位基因的损失是否改变了Parkin Null突变小鼠的CNS表型，反之亦然。目标2：检查帕金和MGRN1是否具有相关的线粒体功能。我们将通过检查破坏MGRN1对线粒体呼吸和形态的影响并确定MGRN1功能的丧失是否会触发Parkin介导的线粒体介导的有线介导的线粒体，从而检验了MGRN1是线粒体伴侣系统的组成部分的假设。我们还将检查MGRN1是否与特定线粒体蛋白的水平相互作用，泛素和/或调节。 公共卫生相关性：神经退行性疾病对受影响的个人，其家庭，医疗保健系统和整个社会产生重大影响。它们具有许多潜在的原因，但是即使已经证明特定蛋白会引起神经退行性，它如何破坏神经元的功能和生存。该提案中概述的工作将有助于我们更多地了解一种称为Mahogunin Ring Finger-1的蛋白质功能，以及它在细胞中是否具有与Parkin相似的功能，在某些具有遗传形式的帕金森氏病的人中，该蛋白质的功能是否相似。我们希望我们的工作将有助于我们了解这些疾病的出现，并最终如何预防或更好地对待它们。