Doctoral Program in Neurobiology and Behavior, Medical Scientist Training Program, Columbia University, New York, NY 10032, USA; Department of Neurology, Columbia University, New York, NY 10032, USA.
Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA; Department of Biosciences, Durham University, Durham DH1 3LE, UK.
Cell Rep. 2022 Oct 18;41(3):111480. doi: 10.1016/j.celrep.2022.111480.
Although macroautophagy deficits are implicated across adult-onset neurodegenerative diseases, we understand little about how the discrete, highly evolved cell types of the central nervous system use macroautophagy to maintain homeostasis. One such cell type is the oligodendrocyte, whose myelin sheaths are central for the reliable conduction of action potentials. Using an integrated approach of mouse genetics, live cell imaging, electron microscopy, and biochemistry, we show that mature oligodendrocytes require macroautophagy to degrade cell autonomously their myelin by consolidating cytosolic and transmembrane myelin proteins into an amphisome intermediate prior to degradation. We find that disruption of autophagic myelin turnover leads to changes in myelin sheath structure, ultimately impairing neural function and culminating in an adult-onset progressive motor decline, neurodegeneration, and death. Our model indicates that the continuous and cell-autonomous maintenance of the myelin sheath through macroautophagy is essential, shedding insight into how macroautophagy dysregulation might contribute to neurodegenerative disease pathophysiology.
虽然巨自噬缺陷与成年发病的神经退行性疾病有关，但我们对中枢神经系统中不同的、高度进化的细胞类型如何利用巨自噬来维持体内平衡知之甚少。少突胶质细胞就是这样一种细胞类型，其髓鞘对动作电位的可靠传导至关重要。我们采用小鼠遗传学、活细胞成像、电子显微镜和生物化学的综合方法，表明成熟的少突胶质细胞需要巨自噬来通过将胞质和跨膜髓鞘蛋白整合到一个自噬体中间体中，然后进行降解，从而自主降解其髓鞘。我们发现，自噬性髓鞘周转率的破坏会导致髓鞘鞘结构发生变化，最终损害神经功能，并导致成年发病的进行性运动衰退、神经退行性变和死亡。我们的模型表明，通过巨自噬对髓鞘进行持续的、细胞自主的维持是必不可少的，这为巨自噬失调如何导致神经退行性疾病的病理生理学提供了新的见解。
