Stavoe Andrea K H, Holzbaur Erika L F
Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States.
Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States.
Neurosci Lett. 2019 Apr 1;697:17-23. doi: 10.1016/j.neulet.2018.03.025. Epub 2018 Mar 13.
Neurons are long-lived and highly polarized cells that depend on autophagy to maintain cellular homeostasis. The robust, constitutive biogenesis of autophagosomes in the distal axon occurs via a conserved pathway that is required to maintain functional synapses and prevent axon degeneration. Autophagosomes are formed de novo at the axon terminal in a stepwise assembly process, engulfing mitochondrial fragments, aggregated proteins, and bulk cytosol in what appears to be a nonselective uptake mechanism. Following formation, autophagosomes fuse with late endosomes/lysosomes and then are rapidly and efficiently transported along the axon toward the soma, driven by the microtubule motor cytoplasmic dynein. Motile autophagosomes mature to autolysosomes in transit by fusing with additional late endosomes/lysosomes, arriving at the soma as fully competent degradative organelles. Misregulation of neuronal autophagy leads to axonal degeneration and synaptic destabilization, and has been implicated in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and ALS.
神经元是长寿且高度极化的细胞，依赖自噬来维持细胞内稳态。轴突远端自噬体的强大、组成型生物发生通过一条保守途径进行，该途径对于维持功能性突触和防止轴突退化是必需的。自噬体在轴突末端通过逐步组装过程从头形成，以一种看似非选择性摄取机制吞噬线粒体片段、聚集蛋白和大量胞质溶胶。形成后，自噬体与晚期内体/溶酶体融合，然后在微管马达细胞质动力蛋白的驱动下沿轴突迅速且高效地向胞体运输。运动性自噬体在运输过程中通过与额外的晚期内体/溶酶体融合成熟为自溶酶体，作为完全有功能的降解细胞器到达胞体。神经元自噬的失调会导致轴突变性和突触不稳定，并与包括阿尔茨海默病、帕金森病、亨廷顿病和肌萎缩侧索硬化症在内的神经退行性疾病有关。
