Autophagic degradation of CNS myelin maintains axon integrity

Authors:

Niki Ktena1, Stefanos Ioannis Kaplanis1, Irina Kolotuev2, Alexandros Georgilis1, Emmanouela Kallergi3, Vasiliki Stavroulaki1, Vassiliki Nikoletopoulou3, Maria Savvaki1, and Domna Karagogeos1
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Affiliations:

1 School of Medicine, University of Crete, Heraklion, Greece.
2 Electron Microscopy Facility (PME), University of Lausanne, Lausanne, Switzerland.
3 Department of Fundamental Neurosciences (DNF), University of Lausanne, Lausanne, Switzerland.

Keywords: 

autophagy, myelin, CNS, oligodendrocyte, PLP, MBP

Corresponding Author(s):

Maria Savvaki, PO Box 1385, Vassilika Vouton, IMBB, Heraklion, GR-71110, Greece msavaki@imbb.forth.gr Domna Karagogeos, PO Box 1385, Vassilika Vouton, IMBB, Heraklion, GR-71110, Greece karagoge@imbb.forth.gr

Conflict of interest statement:

The authors declare that they have no conflict of interest.

Please cite this article as:

Niki Ktena, Stefanos Ioannis Kaplanis, Irina Kolotuev, Alexan-dros Georgilis, Emmanouela Kallergi, Vasiliki Stavroulaki, Vassiliki Nikoletopoulou, Maria Savvaki and Domna Karago-geos (2022). Autophagic degradation of CNS myelin main-tains axon integrity. Cell Stress 6(12): 93-107. doi: 10.15698/cst2022.12.274

© 2022 Ktena et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.

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-CreERT2; 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.