Mechanistic analysis of axonal transport defects in motor neuron degenerative dis

运动神经元退行性疾病轴突运输缺陷的机制分析

基本信息

  • 批准号:
    8079649
  • 负责人:
  • 金额:
    $ 33.76万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-07-01 至 2013-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Abstract Amyotrophic lateral sclerosis (ALS) is a fatal and incurable disease characterized by the degeneration and death of motor neurons. Both sporadic and inherited forms of ALS follow a common pathogenic pathway, which is still not understood. One hypothesis that may explain the motor neuron-specific cell death observed in ALS and other similar neurodegenerative diseases is that motor neurons are uniquely sensitive to defects in axonal transport. Active transport along the axon is driven by microtubule motor proteins; while multiple kinesins drive anterograde transport, cytoplasmic dynein and its activator dynactin are the only motor driving retrograde transport. Dominant mutations in either dynein or dynactin are sufficient to cause motor neuron disease, demonstrating the importance of axonal transport in maintaining healthy motor neurons. We now have data directly demonstrating significant defects in retrograde transport in multiple models of motor neuron disease, including a well- characterized mouse model of familial ALS; defects in dynein localization and function occur as an early event in disease pathogenesis in these models. We will examine the mechanisms linking defects in axonal transport to neurodegeneration, focusing on alterations in both the efficiency of retrograde transport and the nature of the cargos being transported. We hypothesize that these changes act together to lead to alterations in the balance of survival and death signals in the neuron, resulting in neuronal degeneration and cell death. To test this hypothesis, we will pursue three specific aims. In Specific Aim 1, we will look at how dynein-mediated transport is altered during disease onset and progression. We will investigate the specific mechanisms involved by analyzing the motility of proteins and organelles isolated from mouse models of neurodegenerative disease. In Specific Aim 2, we will compare the cargos that are actively transported by dynein in wild type and degenerating neurons, using proteomic screens for dynein cargos. We hypothesize that changes in dynein cargos, especially signaling molecules, will result in alterations in the balance between survival and death signals. Finally, in Specific Aim 3, we will use cellular models of neurodegenerative disease to investigate how defects in axonal transport lead to neurodegeneration. We will examine the relative contributions of defects in the transport machinery and alterations in the cargo being transported, as well as defects in organelle trafficking and protein degradation. The studies proposed here will lead to a clearer understanding of the role of axonal transport in motor neuron degenerative disease. As disruption of intracellular trafficking has been observed in a growing number of degenerative and aging diseases, including Huntington's and Alzheimer's Disease, it is likely that the mechanistic studies proposed here will provide insights that are more broadly applicable to our understanding of neuronal degeneration. PUBLIC HEALTH RELEVANCE: The active movement of proteins, vesicles, and organelles along the extended axons of neurons is called axonal transport. This transport is essential for the health and function of the neuron, and defects in the process cause motor neuron degeneration leading to muscle atrophy in diseases such as Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's Disease). Here, we propose to investigate the mechanisms by which defects in axonal transport, caused either directly by mutations in the motor proteins that drive this transport, or indirectly by the expression of other mutant proteins, lead to degenerative disease.
肌萎缩性侧索硬化症(ALS)是一种以运动神经元变性和死亡为特征的致命且无法治愈的疾病。散发性和遗传性ALS都遵循一个共同的致病途径,这一途径目前仍不清楚。可以解释在ALS和其他类似的神经退行性疾病中观察到的运动神经元特异性细胞死亡的一个假设是运动神经元对轴突运输的缺陷特别敏感。主动运输沿着轴突是由微管马达蛋白驱动的,而多个驱动蛋白驱动顺行运输,细胞质动力蛋白及其激活剂动力蛋白是唯一的马达驱动逆行运输。动力蛋白或动力肌动蛋白的显性突变足以引起运动神经元疾病,证明轴突运输在维持健康运动神经元中的重要性。我们现在有数据直接证明了在多种运动神经元疾病模型中逆行转运的显著缺陷,包括家族性ALS的良好表征的小鼠模型;动力蛋白定位和功能的缺陷作为这些模型中疾病发病机制的早期事件发生。我们将研究轴突运输缺陷与神经退行性变之间的联系机制,重点关注逆行运输效率和运输货物性质的改变。我们假设这些变化共同作用,导致神经元中生存和死亡信号平衡的改变,导致神经元变性和细胞死亡。为了验证这一假设,我们将追求三个具体目标。在具体目标1中,我们将研究在疾病发作和进展期间动力蛋白介导的转运是如何改变的。我们将通过分析从神经退行性疾病小鼠模型中分离的蛋白质和细胞器的运动性来研究所涉及的具体机制。在具体目标2中,我们将使用动力蛋白货物的蛋白质组学筛选来比较动力蛋白在野生型和退化神经元中主动转运的货物。我们假设动力蛋白货物,特别是信号分子的变化,将导致生存和死亡信号之间的平衡改变。最后,在具体目标3中,我们将使用神经退行性疾病的细胞模型来研究轴突运输缺陷如何导致神经退行性疾病。我们将研究运输机械的缺陷和被运输货物的改变,以及细胞器运输和蛋白质降解的缺陷的相对贡献。本文提出的研究将使我们更清楚地了解轴突运输在运动神经元退行性疾病中的作用。由于在越来越多的退行性和衰老性疾病(包括亨廷顿病和阿尔茨海默病)中观察到细胞内运输的中断,因此这里提出的机制研究可能会提供更广泛适用于我们理解神经元变性的见解。公共卫生相关性:蛋白质、囊泡和细胞器沿着神经元延伸轴突的主动运动称为轴突运输。这种转运对于神经元的健康和功能是必不可少的,并且该过程中的缺陷引起运动神经元变性,导致诸如肌萎缩性侧索硬化症(ALS或Lou Gehrig病)的疾病中的肌肉萎缩。在这里,我们建议调查轴突运输缺陷的机制,直接由驱动这种运输的马达蛋白突变引起,或间接由其他突变蛋白的表达引起,导致退行性疾病。

项目成果

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Erika L Holzbaur其他文献

Erika L Holzbaur的其他文献

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{{ truncateString('Erika L Holzbaur', 18)}}的其他基金

Mechanistic analysis of axonal transport defects in neurodegenerative disease
神经退行性疾病轴突运输缺陷的机制分析
  • 批准号:
    9896888
  • 财政年份:
    2018
  • 资助金额:
    $ 33.76万
  • 项目类别:
Molecular Mechanisms of Axonal Transport and Organelle Dynamics
轴突运输和细胞器动力学的分子机制
  • 批准号:
    9922337
  • 财政年份:
    2018
  • 资助金额:
    $ 33.76万
  • 项目类别:
Molecular Mechanisms of Axonal Transport and Organelle Dynamics
轴突运输和细胞器动力学的分子机制
  • 批准号:
    10621591
  • 财政年份:
    2018
  • 资助金额:
    $ 33.76万
  • 项目类别:
Molecular Mechanisms of Axonal Transport and Organelle Dynamics
轴突运输和细胞器动力学的分子机制
  • 批准号:
    10155504
  • 财政年份:
    2018
  • 资助金额:
    $ 33.76万
  • 项目类别:
Mechanistic analysis of axonal transport defects in neurodegenerative disease
神经退行性疾病轴突运输缺陷的机制分析
  • 批准号:
    9617503
  • 财政年份:
    2018
  • 资助金额:
    $ 33.76万
  • 项目类别:
Molecular Mechanisms of Axonal Transport and Organelle Dynamics
轴突运输和细胞器动力学的分子机制
  • 批准号:
    10397408
  • 财政年份:
    2018
  • 资助金额:
    $ 33.76万
  • 项目类别:
Mechanistic analysis of axonal transport defects in motor neuron degenerative dis
运动神经元退行性疾病轴突运输缺陷的机制分析
  • 批准号:
    8270484
  • 财政年份:
    2008
  • 资助金额:
    $ 33.76万
  • 项目类别:
Dynamics of Axonal Autophagy in Neurons
神经元轴突自噬的动力学
  • 批准号:
    10223588
  • 财政年份:
    2008
  • 资助金额:
    $ 33.76万
  • 项目类别:
Mechanistic analysis of axonal transport defects in motor neuron degenerative dis
运动神经元退行性疾病轴突运输缺陷的机制分析
  • 批准号:
    7524459
  • 财政年份:
    2008
  • 资助金额:
    $ 33.76万
  • 项目类别:
Dynamics of Axonal Autophagy in Neurons
神经元轴突自噬的动力学
  • 批准号:
    10610929
  • 财政年份:
    2008
  • 资助金额:
    $ 33.76万
  • 项目类别:

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