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?

基本信息

  • 批准号:
    7878499
  • 负责人:
  • 金额:
    $ 22.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
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.

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Teresa M Gunn其他文献

Teresa M Gunn的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Teresa M Gunn', 18)}}的其他基金

Homeostatic control of the NMDA receptor co-agonist D-serine by SLC1A4
SLC1A4 对 NMDA 受体共激动剂 D-丝氨酸的稳态控制
  • 批准号:
    10366058
  • 财政年份:
    2022
  • 资助金额:
    $ 22.5万
  • 项目类别:
A protein traffic control system that regulates left-right patterning and heart development
调节左右模式和心脏发育的蛋白质交通控制系统
  • 批准号:
    10181808
  • 财政年份:
    2021
  • 资助金额:
    $ 22.5万
  • 项目类别:
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:
    8039080
  • 财政年份:
    2010
  • 资助金额:
    $ 22.5万
  • 项目类别:
Functional analysis of Attractin-Mahogunin signaling
Attractin-Mahogunin 信号传导的功能分析
  • 批准号:
    7249350
  • 财政年份:
    2003
  • 资助金额:
    $ 22.5万
  • 项目类别:

相似海外基金

RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 22.5万
  • 项目类别:
    Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 22.5万
  • 项目类别:
    Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 22.5万
  • 项目类别:
    Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 22.5万
  • 项目类别:
    Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 22.5万
  • 项目类别:
    Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 22.5万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 22.5万
  • 项目类别:
    Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
  • 批准号:
    2301846
  • 财政年份:
    2023
  • 资助金额:
    $ 22.5万
  • 项目类别:
    Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 22.5万
  • 项目类别:
    Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
  • 批准号:
    23K16076
  • 财政年份:
    2023
  • 资助金额:
    $ 22.5万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了