Neuronal Autophagy by the Numbers
Neuronal Autophagy by the Numbers
复制标题
神经元自噬的数据
DOI：
10.1080/27694127.2022.2163091
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Holzbaur, Erika L.
中科院分区：
文献类型：
--
作者：
Cason, Sydney E.;Mogre, Saurabh S.;Koslover, Elena F.;Holzbaur, Erika L.
神经元高度依赖于巨自噬/自噬以在人类90年或更长的寿命内维持细胞稳态。这些细胞有很高的代谢需求，也是高度极化的，轴突可以延伸到一米。总之，这些特征赋予了相当大的压力，突出了自噬等压力缓解途径的重要性。遗传学研究强调了自噬的重要性，因为相关基因的敲除或突变足以诱导神经变性;有缺陷的自噬与神经变性疾病有关，包括帕金森病和肌萎缩性侧索硬化症（ALS）。越来越多的证据表明，与其他细胞类型相比，自噬在神经元中受到差异调节。在非神经元细胞中，自噬通常作为应激反应被激活。然而，在神经元中，有一个强大的基础自噬途径来维持细胞健康。这条通路的整体动力学是很好理解的：自噬体在突触前位点和轴突末端产生。一旦产生，自噬体与晚期内体或溶酶体（统称为内溶酶体）融合，并逐渐成熟成为具有降解能力的细胞器。这些细胞器，统称为自噬囊泡（AV），通过相关的分子马达被招募到轴突微管。在最初的一段时间的双向运动沿着微管，AV过渡到高度进行性，单向运动的索马。这种运动性是由微管负端定向动力蛋白马达驱动的，与DCTN（动力蛋白）和激活衔接子一致。重要的是，随着AV向索马移位，它们继续成熟;成熟促进内化货物的分解和索马内组成大分子的再利用。
Neurons are highly dependent on macroautophagy/autophagy to maintain cellular homeostasis across lifetimes ranging 90 years or more in humans. These cells have high metabolic demands, and are also highly polarized, with axons that can extend up to a meter. Together, these features impart considerable stress, highlighting the importance of stress-relieving pathways such as autophagy. Genetic studies highlight the importance of autophagy, as knockout or mutation of associated genes is sufficient to induce neurodegeneration; defective autophagy is implicated in neurodegenerative diseases including Parkinson and amyotrophic lateral sclerosis (ALS). Accumulating evidence indicates that autophagy is differentially regulated in neurons as compared to other cell types. In non-neuronal cells, autophagy is generally activated as a stress response. In neurons, however, there is a robust pathway for basal autophagy to maintain cellular health. The overall dynamics of this pathway are well understood: autophagosomes are generated at pre-synaptic sites and the axon terminal. Once generated, autophagosomes fuse with late endosomes or lysosomes (collectively, endolysosomes), and gradually mature to become degradatively competent organelles. These organelles, collectively known as autophagic vesicles (AVs), are recruited to axonal microtubules via associated molecular motors. After an initial period of bidirectional motility along the microtubule, AVs transition to highly processive, unidirectional motility toward the soma. This motility is driven by the microtubule minus-end-directed dynein motor, in concert with DCTN (dynactin) and activating adaptors. Importantly, as AVs are translocated toward the soma, they continue to mature; maturation facilitates the breakdown of internalized cargo and the reuse of constituent macromolecules within the soma.