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: 7722267
• 负责人: Qingjun Wang
• 金额: $ 1.66万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7722267
• 关键词: Ablation; Atrophic; Autophagocytosis; Autophagosome; Axon; Behavioral; Cell Death; Cells; Computer Retrieval of Information on Scientific Projects Database; Condition; Dendrites; Event; Funding; Genes; Grant; Homeostasis; Impairment; Institution; Knock-out; Maintenance; Membrane; Membrane Protein Traffic; Mus; Mutant Strains Mice; Nerve Degeneration; Neurons; Presynaptic Terminals; Prevention; Process; Proteins; Purkinje Cells; Reporting; Research; Research Personnel; Resources; Role; Source; Structure; Swelling; United States National Institutes of Health; Vacuole; Vertebral column; axonopathy; 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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 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转运。虽然最近的证据表明，基础水平的自噬可以防止神经变性，但这种情况发生的确切机制尚不清楚。通过使用条件性基因敲除突变小鼠，我们报告说，神经元自噬是特别重要的轴突终末的局部稳态的维持和保护轴突变性。我们发现，一个必不可少的自噬基因，Atg 7，在浦肯野细胞的特异性消融最初会导致细胞自主，进行性营养不良（表现为轴突sodium）和轴突终端的变性。与自噬的抑制一致，在这些营养不良的sendulum中没有观察到自噬体，这与在病理条件下轴突营养不良的sendulum中自噬体的积累相反。突变型浦肯野细胞的轴突营养不良几乎没有树突或棘萎缩的迹象，表明轴突末梢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，突变体浦肯野细胞的超微结构分析揭示了异常的膜结构的轴突营养不良性sodium的积累。最后，我们观察到野生型浦肯野细胞轴突中的双膜空泡样结构，而这些结构在突变体浦肯野细胞轴突中被废除。因此，我们的结论是，自噬蛋白Atg 7所需的膜贩运和营业额的轴突。我们的研究暗示轴突自噬损伤是与神经退行性变相关的轴突病的可能机制。