Role of mitochondrial GDAP1 in Alzheimer's disease

线粒体 GDAP1 在阿尔茨海默病中的作用

基本信息

  • 批准号:
    10739858
  • 负责人:
  • 金额:
    $ 67.51万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-08-15 至 2028-04-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Despite extensive research, we still do not fully understand how neurons die in Alzheimer’s disease (AD) patients' brains after withstanding decades of the accumulation of AD pathology. Oxidative damage and mitochondrial deficits are proposed to contribute to or drive neurodegeneration in AD. AD brains show an accumulation of the toxic end-product of lipid peroxidation 4-hydroxynoneal (4HNE), but it remains unclear what causes 4HNE to accumulate in AD. Moreover, a mechanistic understanding of the increased sensitivity of mitochondria and neurons in AD to oxidative damage is lacking. We determined that an atypical member of the glutathione S- transferase (GST) superfamily, GDAP1 (Ganglioside Induced Differentiation Associated Protein 1), binds 4HNE through a unique sequence motif called the α-loop, which is also essential for GDAP1 function. These data collectively indicate that 4HNE is a GDAP1 substrate and that 4HNE binding to GDAP1 is essential for the maintenance of cellular redox balance and mitochondrial function. Significantly, our preliminary RNAseq data from AD patients and analysis of four AD proteomic datasets show significantly reduced levels of GDAP1 in the prefrontal cortex of AD patients. As such, we hypothesize that GDAP1 protects mitochondria against oxidative damage by neutralizing the highly toxic 4HNE and that reduced levels of GDAP1 render AD patient brains vulnerable to 4HNE-mediated damage. We will test this hypothesis with two Aims. Aim 1 will determine the mechanism of GDAP1-mediated cryoprotection including the mechanisms of 4HNE binding and detoxification. Aim 2 will determine the impact of reduced levels of GDAP1 on mitochondrial function and accumulation of the pathological hallmarks of AD in directly converted induced neurons from control subjects and AD patients. These studies will establish the relationship between reduced GDAP1 levels, elevated 4HNE levels, and the increased vulnerability of neurons in AD patients to oxidative damage and open a potential avenue for therapeutic intervention in AD.
项目摘要 尽管进行了广泛的研究,我们仍然没有完全了解阿尔茨海默病(AD)患者的神经元是如何死亡的。 大脑在经受了几十年AD病理的积累后。氧化损伤与线粒体 缺陷被认为有助于或驱动AD中的神经变性。AD患者的大脑中, 脂质过氧化的有毒终产物4-羟基壬烯醛(4HNE),但目前还不清楚是什么原因导致4HNE 在AD中积累。此外,对线粒体敏感性增加的机制理解, AD中的神经元缺乏氧化损伤。我们确定谷胱甘肽S- 转移酶(GST)超家族GDAP 1(神经节苷脂诱导分化相关蛋白1)结合4HNE 通过称为α环的独特序列基序,这也是GDAP 1功能所必需的。这些数据 这共同表明4HNE是GDAP 1底物,并且4HNE与GDAP 1的结合对于GDAP 1的表达是必需的。 维持细胞氧化还原平衡和线粒体功能。值得注意的是,我们的初步RNAseq数据 从AD患者和四个AD蛋白质组数据集的分析显示,在AD患者中GDAP 1水平显著降低, AD患者的前额皮质。因此,我们假设GDAP 1保护线粒体免受氧化损伤, 通过中和高毒性4HNE和降低GDAP 1水平使AD患者的大脑 易受4HNE介导的损伤。我们将用两个目标来检验这个假设。目标1将决定 GDAP 1介导的冷冻保护机制包括4HNE结合和解毒机制。 目的2将确定降低的GDAP 1水平对线粒体功能和线粒体膜电位的积累的影响。 AD的病理标志在直接转换的诱导神经元从对照组和AD患者。这些 研究将建立GDAP 1水平降低、4HNE水平升高和4HNE水平升高之间的关系。 AD患者神经元对氧化损伤的脆弱性,并为治疗AD开辟了潜在的途径。 在AD中的干预

项目成果

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KIRILL KISELYOV其他文献

KIRILL KISELYOV的其他文献

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{{ truncateString('KIRILL KISELYOV', 18)}}的其他基金

The TRPML1 Role in Lysosomes
TRPML1 在溶酶体中的作用
  • 批准号:
    8337338
  • 财政年份:
    2011
  • 资助金额:
    $ 67.51万
  • 项目类别:
The TRPML1 Role in Lysosomes
TRPML1 在溶酶体中的作用
  • 批准号:
    8243335
  • 财政年份:
    2011
  • 资助金额:
    $ 67.51万
  • 项目类别:
The TRPML1 Role in Lysosomes
TRPML1 在溶酶体中的作用
  • 批准号:
    8527812
  • 财政年份:
    2011
  • 资助金额:
    $ 67.51万
  • 项目类别:
The TRPML1 Role in Lysosomes
TRPML1 在溶酶体中的作用
  • 批准号:
    7936220
  • 财政年份:
    2009
  • 资助金额:
    $ 67.51万
  • 项目类别:
The TRPML1 Role in Lysosomes
TRPML1 在溶酶体中的作用
  • 批准号:
    7651968
  • 财政年份:
    2009
  • 资助金额:
    $ 67.51万
  • 项目类别:
The Role of Mucolipin 1 Block in Transition Metal Toxicity
Mucolipin 1 嵌段在过渡金属毒性中的作用
  • 批准号:
    7658637
  • 财政年份:
    2009
  • 资助金额:
    $ 67.51万
  • 项目类别:
The Role of Mucolipin 1 Block in Transition Metal Toxicity
Mucolipin 1 嵌段在过渡金属毒性中的作用
  • 批准号:
    7816743
  • 财政年份:
    2009
  • 资助金额:
    $ 67.51万
  • 项目类别:

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