RT Journal Article
SR Electronic
T1 Autophagy degrades myelin proteins and is essential for maintaining CNS myelin homeostasis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.06.20.496817
DO 10.1101/2022.06.20.496817
A1 Niki Ktena
A1 Stefanos Ioannis Kaplanis
A1 Irina Kolotuev
A1 Alexandros Georgilis
A1 Vasiliki Stavroulaki
A1 Emmanouela Kallergi
A1 Vassiliki Nikoletopoulou
A1 Domna Karagogeos
A1 Maria Savvaki
YR 2022
UL http://biorxiv.org/content/early/2022/06/21/2022.06.20.496817.abstract
AB (Macro)autophagy comprises 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; atg5F/F) at two distinct stages. Depletion of autophagy before the initiation of myelination does not impair the myelin status; however, myelin maintenance is perturbed upon autophagic ablation during adulthood, 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.Competing Interest StatementThe authors have declared no competing interest.