Dynamics of Axonal Autophagy in Neurons

神经元轴突自噬的动力学

基本信息

  • 批准号:
    10610929
  • 负责人:
  • 金额:
    $ 42.71万
  • 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 2026-03-31
  • 项目状态:
    未结题

项目摘要

Project Summary Autophagy is an essential cellular degradative pathway triggered by environmental stress in many cell types. In neurons, autophagy has a further role as a constitutively active mechanism that maintains axonal homeostasis. In vitro and in vivo, autophagosomes are generated de novo at axon terminals and synaptic sites. Once formed, axonal autophagosomes are trafficked back to the soma by the retrograde microtubule motor protein cytoplasmic dynein. Autophagosomes mature en route through fusion with late endosomes and lysosomes. Cargo degradation also occurs during transport along the axon, leading to the somal delivery of digested contents for recycling in new biosynthetic pathways. Axonal autophagy degrades mitochondrial fragments and disease- associated protein aggregates, suggesting a key role in the maintenance of axonal homeostasis. Consistent with this hypothesis, neuron-specific ablation of autophagy is sufficient to cause neurodegeneration. However, many outstanding questions remain that must be addressed: How is autophagy regulated in neurons? What controls the localization and timing of autophagosome formation and cargo engulfment? What is the function of axonal autophagy – what cargos are targeted for degradation, and by what mechanisms? And how does the axonal autophagy pathway intersect with the endolysosomal pathway to effectively degrade cargos such as dysfunctional organelles and aggregated proteins? To address these questions, we will use live cell imaging in primary neurons and gene-edited iPSC-derived human neurons, in concert with biochemical and biophysical approaches including proteomic analysis and computational modeling, to query the basic mechanisms of axonal autophagy and how these mechanisms are perturbed by neuronal stressors including mitochondrial dysfunction, protein aggregation, and lysosomal damage. We will address the following specific aims: Aim 1: How is autophagy spatially and temporally regulated in neurons? What controls the initiation of autophagy at the axon terminal or presynaptic sites? Aim 2: What cargos are degraded by axonal autophagy? Is cargo engulfment a selective process, or nonspecific? Is there preferential uptake of some cargos, and if so, what are these cargos? What mechanisms control cargo uptake? And Aim 3: How does the autophagy pathway intersect with the lysosomal pathway? How is autophagosome-lysosome fusion regulated? Why is axonal autophagy so dependent on retrograde axonal transport? And what mechanisms regulate lysosomal health along the axon, as lysosomes are required for the effective clearance of engulfed cargos by autophagy. Given the essential and conserved role that autophagy plays in neurons, we anticipate that these studies will significantly advance our understanding of neuronal cell biology, providing important insights into the mechanisms maintaining axonal. homeostasis and how the perturbation of these mechanisms may lead to neurodegeneration. We hope that these advances will provide new ideas on how to best intervene therapeutically to treat diseases such as ALS, Huntington's, and Parkinson's disease.
项目摘要 自噬是许多细胞类型中由环境应激引发的一种重要的细胞降解途径。在……里面 对于神经元,自噬作为一种维持轴突内稳态的结构性活跃机制具有进一步的作用。 在体外和体内,自噬小体在轴突终末和突触位置从头产生。一旦形成, 轴突自噬小体通过逆行微管运动蛋白细胞质运输回胞体 动力蛋白。自噬小体在与晚期内噬小体和溶酶体融合的过程中成熟。货货 在沿着轴突的运输过程中也会发生降解,导致消化的内容物在胞体内传递 在新的生物合成途径中回收利用。轴突自噬降解线粒体碎片和疾病- 相关的蛋白质聚集,表明在维持轴突内稳态中起关键作用。与一致 这一假说,神经元特异性自噬的消融足以引起神经变性。然而,许多人 悬而未决的问题仍然是必须解决的:神经元中的自噬是如何调节的?是什么控制着 自噬小体的形成和货物吞没的定位和时间?轴突的功能是什么 自噬--哪些货物是降解的目标,通过什么机制?轴突是如何 自噬途径与内溶酶体途径相交,有效地降解货物,如 功能失调的细胞器和聚集的蛋白质?为了解决这些问题,我们将使用活细胞成像技术 原代神经元和经基因编辑的IPSC来源的人类神经元,结合生化和生物物理 质疑轴突基本机制的方法包括蛋白质组学分析和计算模型 自噬以及这些机制是如何被包括线粒体功能障碍在内的神经元应激源扰乱的, 蛋白质聚集和溶酶体损伤。我们将解决以下具体目标:目标1:情况如何 自噬在空间和时间上对神经元的调节?是什么控制了轴突自噬的启动 终末或突触前部位?目的2:轴突自噬能降解哪些物质?货物吞没是一种 是选择性的过程,还是非特定的?是否优先接收某些货物?如果是,这些货物是什么? 控制货物吸收的机制是什么?目标3:自噬途径如何与 溶酶体途径?自噬小体-溶酶体融合是如何调控的?为什么轴突自噬如此严重 依赖逆行轴突运输?以及沿轴突调节溶酶体健康的机制, 因为通过自噬有效清除吞噬的货物需要溶酶体。考虑到基本的和 自噬在神经元中扮演着保守的角色,我们预计这些研究将显著促进我们的 了解神经细胞生物学,为维持轴突的机制提供重要的见解。 动态平衡以及这些机制的扰动如何导致神经退化。我们希望这些 新的进展将为如何最好地干预治疗以治疗ALS等疾病提供新的想法, 亨廷顿氏症和帕金森氏症。

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:
    $ 42.71万
  • 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:
    $ 42.71万
  • 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:
    $ 42.71万
  • 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:
    $ 42.71万
  • 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:
    $ 42.71万
  • 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:
    $ 42.71万
  • 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:
    $ 42.71万
  • 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:
    $ 42.71万
  • 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:
    $ 42.71万
  • 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:
    8079649
  • 财政年份:
    2008
  • 资助金额:
    $ 42.71万
  • 项目类别:

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