Department of Neurobiology & Anatomy, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Autophagy. 2023 Dec;19(12):3079-3095. doi: 10.1080/15548627.2023.2236485. Epub 2023 Jul 18.
Misregulation of neuronal macroautophagy/autophagy has been implicated in age-related neurodegenerative diseases. We compared autophagosome formation and maturation in primary murine neurons during development and through aging to elucidate how aging affects neuronal autophagy. We observed an age-related decrease in the rate of autophagosome formation leading to a significant decrease in the density of autophagosomes along the axon. Next, we identified a surprising increase in the maturation of autophagic vesicles in neurons from aged mice. While we did not detect notable changes in endolysosomal content in the distal axon during early aging, we did observe a significant loss of acidified vesicles in the distal axon during late aging. Interestingly, we found that autophagic vesicles were transported more efficiently in neurons from adult mice than in neurons from young mice. This efficient transport of autophagic vesicles in both the distal and proximal axon is maintained in neurons during early aging, but is lost during late aging. Our data indicate that early aging does not negatively impact autophagic vesicle transport nor the later stages of autophagy. However, alterations in autophagic vesicle transport efficiency during late aging reveal that aging differentially impacts distinct aspects of neuronal autophagy. ACAP3: ArfGAP with coiled-coil, ankyrin repeat and PH domains 3; ARF6: ADP-ribosylation factor 6; ATG: autophagy related; AVs: autophagic vesicles; DCTN1/p150: dynactin 1; DRG: dorsal root ganglia; GAP: GTPase activating protein; GEF: guanine nucleotide exchange factor; LAMP2: lysosomal-associated protein 2; LysoT: LysoTracker; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MAPK8IP1/JIP1: mitogen-activated protein kinase 8 interacting protein 1; MAPK8IP3/JIP3: mitogen-activated protein kinase 8 interacting protein 3; mCh: mCherry; PE: phosphatidylethanolamine.
神经元巨自噬/自噬的失调与年龄相关的神经退行性疾病有关。我们比较了在发育过程中和衰老过程中原代小鼠神经元中的自噬体形成和成熟，以阐明衰老如何影响神经元自噬。我们观察到自噬体形成的速率与年龄相关下降，导致沿轴突的自噬体密度显著降低。接下来，我们发现衰老小鼠神经元中自噬小体的成熟率出人意料地增加。虽然我们在早期衰老过程中没有检测到远端轴突中内溶酶体含量的显著变化，但我们确实观察到晚期衰老过程中远端轴突中酸化小体的显著丢失。有趣的是，我们发现自噬小体在成年小鼠神经元中的运输效率比在幼年小鼠神经元中更高。这种自噬小体在远端和近端轴突中的有效运输在早期衰老的神经元中得以维持，但在晚期衰老的神经元中丢失。我们的数据表明，早期衰老不会对自噬小体运输或自噬的后期阶段产生负面影响。然而，晚期衰老过程中自噬小体运输效率的改变表明，衰老对神经元自噬的不同方面有不同的影响。ACAP3：含卷曲螺旋、锚蛋白重复和 PH 结构域的 ArfGAP3；ARF6：ADP-核糖基化因子 6；ATG：自噬相关；AVs：自噬小体；DCTN1/p150：动力蛋白 1 重链；DRG：背根神经节；GAP：GTP 酶激活蛋白；GEF：鸟嘌呤核苷酸交换因子；LAMP2：溶酶体相关蛋白 2；LysoT：LysoTracker；MAP1LC3B/LC3B：微管相关蛋白 1 轻链 3B；MAPK8IP1/JIP1：丝裂原活化蛋白激酶 8 相互作用蛋白 1；MAPK8IP3/JIP3：丝裂原活化蛋白激酶 8 相互作用蛋白 3；mCh：mCherry；PE：磷脂酰乙醇胺。
