ESSENTIAL ROLE FOR AUTOPHAGY PROTEIN ATG7 THE PREVENTION OF AXONAL DEGENERATION

自噬蛋白 ATG7 在预防轴突变性中的重要作用

• 批准号: 7954117
• 负责人: Qingjun Wang
• 金额: $ 0.36万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7954117
• 关键词: Ablation; Atrophic; Autophagocytosis; Autophagosome; Axon; Behavioral; Cell Death; Cells; Computer Retrieval of Information on Scientific Projects Database; Dendrites; Event; Funding; Genes; Grant; Homeostasis; Impairment; Institution; Knock-out; Maintenance; Manuscripts; Membrane; Membrane Protein Traffic; Mus; Mutant Strains Mice; Nerve Degeneration; Neurons; Presynaptic Terminals; Prevention; Process; Proteins; Publishing; Purkinje Cells; Reporting; Research; Research Personnel; Resources; Role; Source; Structure; Swelling; United States National Institutes of Health; Vacuole; Vertebral column; Work; axonal degeneration; axonopathy; macromolecule; mutant

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Autophagy is a regulated lysosomal degradation process that involves autophagosome formation and transport. Although recent evidence indicates that basal levels of autophagy protect against neurodegeneration, the exact mechanism whereby this occurs is not known. By using conditional knockout mutant mice, we report that neuronal autophagy is particularly important for the maintenance of local homeostasis of axon terminals and protection against axonal degeneration. We show that specific ablation of an essential autophagy gene, Atg7, in Purkinje cells initially causes cell-autonomous, progressive dystrophy (manifested by axonal swellings) and degeneration of the axon terminals. Consistent with suppression of autophagy, no autophagosomes are observed in these dystrophic swellings, which is in contrast to accumulation of autophagosomes in the axonal dystrophic swellings under pathological conditions. Axonal dystrophy of mutant Purkinje cells proceeds with little sign of dendritic or spine atrophy, indicating that axon terminals are much more vulnerable to autophagy impairment than dendrites. This early pathological event in the axons is followed by cell-autonomous Purkinje cell death and mouse behavioral deficits. Furthermore, ultrastructural analyses of mutant Purkinje cells reveal an accumulation of aberrant membrane structures in the axonal dystrophic swellings. Finally, we observe double-membrane vacuole-like structures in wild-type Purkinje cell axons, whereas these structures are abolished in mutant Purkinje cell axons. Thus, we conclude that the autophagy protein Atg7 is required for membrane trafficking and turnover in the axons. Our study implicates impairment of axonal autophagy as a possible mechanism for axonopathy associated with neurodegeneration. A manuscript describing this work was published: Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration. Komatsu M, Wang QJ, Holstein GR, Friedrich VL Jr, Iwata J, Kominami E, Chait BT, Tanaka K, Yue Z. Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14489-94.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 自噬是一种受调节的溶酶体降解过程，涉及自噬体的形成和运输。尽管最近的证据表明自噬的基础水平可以防止神经变性，但发生这种情况的确切机制尚不清楚。通过使用条件敲除突变小鼠，我们报告神经元自噬对于维持轴突末端的局部稳态和防止轴突变性特别重要。我们发现，浦肯野细胞中必需的自噬基因 Atg7 的特异性消融最初会导致细胞自主的进行性营养不良（表现为轴突肿胀）和轴突末端的退化。与自噬的抑制一致，在这些营养不良性肿胀中没有观察到自噬体，这与病理条件下轴突营养不良性肿胀中自噬体的积累相反。突变浦肯野细胞的轴突营养不良几乎没有树突或脊柱萎缩的迹象，这表明轴突末端比树突更容易受到自噬损伤。轴突中的这种早期病理事件之后是细胞自主性浦肯野细胞死亡和小鼠行为缺陷。此外，突变浦肯野细胞的超微结构分析揭示了轴突营养不良性肿胀中异常膜结构的积累。最后，我们在野生型浦肯野细胞轴突中观察到双膜液泡样结构，而这些结构在突变型浦肯野细胞轴突中被消除。因此，我们得出结论，自噬蛋白 Atg7 是轴突膜运输和周转所必需的。我们的研究表明轴突自噬受损是与神经退行性疾病相关的轴突病的可能机制。描述这项工作的手稿已发表：自噬蛋白 Atg7 在维持轴突稳态和预防轴突变性中的重要作用。 Komatsu M、Wang QJ、Holstein GR、Friedrich VL Jr、Iwata J、Kominami E、Chait BT、Tanaka K、Yue Z。Proc Natl Acad Sci U S A. 2007 年 9 月 4 日；104(36)：14489-94。