Autophagic degradation of CNS myelin maintains axon integrity.

IF 4.1 Q2 CELL BIOLOGY Cell Stress Pub Date : 2022-12-01 DOI:10.15698/cst2022.12.274
Niki Ktena, Stefanos Ioannis Kaplanis, Irina Kolotuev, Alexandros Georgilis, Emmanouela Kallergi, Vasiliki Stavroulaki, Vassiliki Nikoletopoulou, Maria Savvaki, Domna Karagogeos
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引用次数: 6

Abstract

(Macro)autophagy is a major lysosome-dependent degradation mechanism which engulfs, removes and recycles unwanted cytoplasmic material, including damaged organelles and toxic protein aggregates. Although a few studies implicate autophagy in CNS demyelinating pathologies, its role, particularly in mature oligodendrocytes and CNS myelin, remains poorly studied. Here, using both pharmacological and genetic inhibition of the autophagic machinery, we provide evidence that autophagy is an essential mechanism for oligodendrocyte maturation in vitro. Our study reveals that two core myelin proteins, namely proteolipid protein (PLP) and myelin basic protein (MBP) are incorporated into autophagosomes in oligodendrocytes, resulting in their degradation. Furthermore, we ablated atg5, a core gene of the autophagic machinery, specifically in myelinating glial cells in vivo by tamoxifen administration (plp-Cre ERT2 ; atg5 f/f ) and showed that myelin maintenance is perturbed, leading to PLP accumulation. Significant morphological defects in myelin membrane such as decompaction accompanied with increased axonal degeneration are observed. As a result, the mice exhibit behavioral deficits. In summary, our data highlight that the maintenance of adult myelin homeostasis in the CNS requires the involvement of a fully functional autophagic machinery.

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中枢神经系统髓磷脂的自噬降解维持轴突的完整性。
(宏观)自噬是一种主要的依赖溶酶体的降解机制,它吞噬、去除和循环不需要的细胞质物质,包括受损的细胞器和有毒的蛋白质聚集体。尽管有一些研究表明自噬与中枢神经系统脱髓鞘病理有关,但其作用,特别是在成熟少突胶质细胞和中枢神经系统髓鞘中的作用仍未得到充分研究。本研究通过对自噬机制的药理学和遗传抑制,证明自噬是体外少突胶质细胞成熟的重要机制。我们的研究表明,两种核心髓磷脂蛋白,即蛋白脂质蛋白(PLP)和髓鞘碱性蛋白(MBP)被纳入少突胶质细胞的自噬体,导致其降解。此外,我们通过给药他莫昔芬(plp-Cre ERT2;atg5 f/f),显示髓磷脂维持受到干扰,导致PLP积累。髓鞘膜有明显的形态学缺陷,如失压,伴轴突变性增加。结果,老鼠表现出行为缺陷。总之,我们的数据强调了中枢神经系统中成人髓磷脂稳态的维持需要一个功能完备的自噬机制的参与。
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来源期刊
Cell Stress
Cell Stress Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (miscellaneous)
CiteScore
13.50
自引率
0.00%
发文量
21
审稿时长
15 weeks
期刊介绍: Cell Stress is an open-access, peer-reviewed journal that is dedicated to publishing highly relevant research in the field of cellular pathology. The journal focuses on advancing our understanding of the molecular, mechanistic, phenotypic, and other critical aspects that underpin cellular dysfunction and disease. It specifically aims to foster cell biology research that is applicable to a range of significant human diseases, including neurodegenerative disorders, myopathies, mitochondriopathies, infectious diseases, cancer, and pathological aging. The scope of Cell Stress is broad, welcoming submissions that represent a spectrum of research from fundamental to translational and clinical studies. The journal is a valuable resource for scientists, educators, and policymakers worldwide, as well as for any individual with an interest in cellular pathology. It serves as a platform for the dissemination of research findings that are instrumental in the investigation, classification, diagnosis, and therapeutic management of major diseases. By being open-access, Cell Stress ensures that its content is freely available to a global audience, thereby promoting international scientific collaboration and accelerating the exchange of knowledge within the research community.
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