Mitochondrial Sirtuin 3 in Parkinson's disease

线粒体 Sirtuin 3 在帕金森病中的作用

基本信息

  • 批准号:
    10686813
  • 负责人:
  • 金额:
    $ 47.65万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-06-01 至 2025-05-31
  • 项目状态:
    未结题

项目摘要

The overall aim of this application is to investigate mechanisms of alpha-synuclein (αsyn)-induced mitochondrial dysfunction in Lewy body diseases (LBD). Despite its predominant localization in the cytosol, αsyn localizes to mitochondria in post-mortem LBD brains. Within the mitochondria, αsyn accumulation can impair complex I and IV function, decrease membrane potential, increase levels of reactive oxygen species, and increase apoptosis associated with cytochrome c release from the mitochondria. Together these data suggest an increase in mitochondrial αsyn expression and/or abnormal accumulation of toxic aggregates interferes with mitochondrial function. Maintaining mitochondrial health is essential to prevent neuronal cell death in the brain. Sirtuin 3 (SIRT3) is a NAD+-dependent protein deacetylase exclusively localized to the mitochondria where it regulates mitochondrial processes including protein deacetylation, organelle biogenesis, and oxidative stress. SIRT3 is expressed at high levels in the brain and other nervous system tissues, and can act as a pro- survival factor, playing an essential role in protecting neurons under conditions of excitotoxicity and rescuing neuronal loss in neurodegenerative models. Experimental evidence indicates that SIRT3- induced neuroprotection against oxidative stress is partially mediated by enhancement of mitochondrial biogenesis and integrity. As we consider sirtuin-based drug therapies for diseases of ageing, it is important to determine if modulating SIRT3 can protect against neurodegeneration where mitochondrial dysfunction has been demonstrated to play a role. This proposal will investigate how mitochondrial SIRT3 contributes to αsyn-induced mitochondrial dysfunction in 3 coordinated aims. In aim 1 we will perform comprehensive mitochondrial function analyses to reveal how αsyn accumulation leads to mitochondrial damage and the role of SIRT3 therein using patient-derived cells and postmortem brain. In aim 2 we will interrogate the SIRT3 regulated acetylome to identify novel targets of αsyn-associated mitochondrial dysfunction, and in aim 3 we will validate SIRT3 as a novel target for therapeutic intervention in PD in a comprehensive in vivo approach using genetic overexpression and pharmacological activation. The proposed rigorous analysis of various mitochondrial aspects will dissect causes from consequences and reveal the cross-talk between αsyn, SIRT3, and mitochondrial signaling pathways as well as oxidative and protein stress responses.
本应用程序的总体目的是研究α -突触核蛋白(αsyn)诱导的机制

项目成果

期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Cellular models of alpha-synuclein toxicity and aggregation.
  • DOI:
    10.1111/jnc.14806
  • 发表时间:
    2019-09
  • 期刊:
  • 影响因子:
    4.7
  • 作者:
    Delenclos M;Burgess JD;Lamprokostopoulou A;Outeiro TF;Vekrellis K;McLean PJ
  • 通讯作者:
    McLean PJ
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Pamela J McLean其他文献

Pamela J McLean的其他文献

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{{ truncateString('Pamela J McLean', 18)}}的其他基金

Mitochondrial Sirtuin 3 in Parkinson's disease
线粒体 Sirtuin 3 在帕金森病中的作用
  • 批准号:
    10409706
  • 财政年份:
    2019
  • 资助金额:
    $ 47.65万
  • 项目类别:
Functional assessment of pathological α-syn and Aβ species in LBD
LBD 中病理 α-syn 和 Aβ 物种的功能评估
  • 批准号:
    10237303
  • 财政年份:
    2019
  • 资助金额:
    $ 47.65万
  • 项目类别:
Mitochondrial Sirtuin 3 in Parkinson's disease
线粒体 Sirtuin 3 在帕金森病中的作用
  • 批准号:
    10348483
  • 财政年份:
    2019
  • 资助金额:
    $ 47.65万
  • 项目类别:
Functional assessment of pathological α-syn and Aβ species in LBD
LBD 中病理 α-syn 和 Aβ 物种的功能评估
  • 批准号:
    10022185
  • 财政年份:
    2019
  • 资助金额:
    $ 47.65万
  • 项目类别:
Functional assessment of pathological α-syn and Aβ species in LBD
LBD 中病理 α-syn 和 Aβ 物种的功能评估
  • 批准号:
    10478195
  • 财政年份:
    2019
  • 资助金额:
    $ 47.65万
  • 项目类别:
Mitochondrial Sirtuin 3 in Parkinson's disease
线粒体 Sirtuin 3 在帕金森病中的作用
  • 批准号:
    9753438
  • 财政年份:
    2019
  • 资助金额:
    $ 47.65万
  • 项目类别:
Functional assessment of pathological α-syn and Aβ species in LBD
LBD 中病理 α-syn 和 Aβ 物种的功能评估
  • 批准号:
    10686906
  • 财政年份:
    2019
  • 资助金额:
    $ 47.65万
  • 项目类别:
Mitochondrial Sirtuin 3 in Parkinson's disease
线粒体 Sirtuin 3 在帕金森病中的作用
  • 批准号:
    10161872
  • 财政年份:
    2019
  • 资助金额:
    $ 47.65万
  • 项目类别:
Extracellular alpha-synuclein in Parkinson's Disease
帕金森病中的细胞外 α-突触核蛋白
  • 批准号:
    8234547
  • 财政年份:
    2011
  • 资助金额:
    $ 47.65万
  • 项目类别:
Extracellular alpha-synuclein in Parkinson's Disease
帕金森病中的细胞外 α-突触核蛋白
  • 批准号:
    8695502
  • 财政年份:
    2011
  • 资助金额:
    $ 47.65万
  • 项目类别:

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