Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland.
Department of Biology, University of Fribourg, 1700 Fribourg, Switzerland.
Neuron. 2023 Aug 2;111(15):2329-2347.e7. doi: 10.1016/j.neuron.2023.05.011. Epub 2023 Jun 5.
Autophagy disorders prominently affect the brain, entailing neurodevelopmental and neurodegenerative phenotypes in adolescence or aging, respectively. Synaptic and behavioral deficits are largely recapitulated in mouse models with ablation of autophagy genes in brain cells. Yet, the nature and temporal dynamics of brain autophagic substrates remain insufficiently characterized. Here, we immunopurified LC3-positive autophagic vesicles (LC3-pAVs) from the mouse brain and proteomically profiled their content. Moreover, we characterized the LC3-pAV content that accumulates after macroautophagy impairment, validating a brain autophagic degradome. We reveal selective pathways for aggrephagy, mitophagy, and ER-phagy via selective autophagy receptors, and the turnover of numerous synaptic substrates, under basal conditions. To gain insight into the temporal dynamics of autophagic protein turnover, we quantitatively compared adolescent, adult, and aged brains, revealing critical periods of enhanced mitophagy or degradation of synaptic substrates. Overall, this resource unbiasedly characterizes the contribution of autophagy to proteostasis in the maturing, adult, and aged brain.
自噬障碍显著影响大脑，分别导致青少年或衰老时的神经发育和神经退行性表型。在脑细胞中敲除自噬基因的小鼠模型中，突触和行为缺陷得到了很大程度的重现。然而，脑自噬底物的性质和时间动态仍未得到充分描述。在这里，我们从小鼠脑中免疫纯化 LC3 阳性自噬小体 (LC3-pAV)，并对其内容物进行蛋白质组学分析。此外，我们还对巨自噬受损后积累的 LC3-pAV 含量进行了特征分析，验证了脑自噬降解组。我们通过选择性自噬受体揭示了聚集自噬、线粒体自噬和内质网自噬的选择性途径，以及在基础条件下许多突触底物的周转。为了深入了解自噬蛋白周转的时间动态，我们定量比较了青少年、成年和老年大脑，揭示了增强线粒体自噬或突触底物降解的关键时期。总的来说，这项资源无偏地描述了自噬对成熟、成年和老年大脑中蛋白质稳定性的贡献。
