AUTOPHAGY-DEPENDENT MECHANISMS IN OLIGODENDROCYTE MATURATION AND WHITE MATTER INTEGRITY

Autophagy is a key cellular mechanism supporting adaptation to the metabolic and structural demands associated with oligodendrocyte maturation and white matter maintenance. However, how alterations in autophagy-lysosome pathways impact oligodendrocyte physiology remains incompletely understood. Here, we investigated the role of autophagy in oligodendrocyte maturation using complementary in vivo genetic and in vitro pharmacological approaches.
In vivo, mice with constitutively reduced autophagic flux due to ATG4B deficiency exhibited reduced numbers of OLIG2⁺ cells and a tendency towards decreased APC-CC1⁺ oligodendrocytes specifically in the corpus callosum, with no detectable changes in the adjacent cortex, indicating that intact autophagic activity is required to sustain the oligodendrocyte lineage in white matter. Ongoing analyses aim to further define the affected maturation stage by examining progenitor populations and myelin-related markers.
In vitro, oligodendrocyte differentiation was associated with a consistent increase in autophagic flux together with an expansion of SCARB2⁺ cytoplasmic compartments, suggesting enhanced engagement of autophagy-lysosome pathways during maturation. Pharmacological modulation of these pathways altered the organization of SCARB2⁺ compartments. Functionally, inhibition of autophagy with MRT68921 or inhibition of SCARB2 with tetrandrine impaired oligodendroglial differentiation and reduced autophagic flux, whereas induction of autophagy with metformin or inhibition of glucocerebrosidase with conduritol b-epoxide did not affect autophagic activity or maturation, indicating selective requirements within the autophagy-lysosome system.
Together, these findings support the idea that oligodendrocyte maturation and physiology depend on a finely regulated and selective organization of the autophagy-lysosome compartment, providing a framework to understand how oligodendrocyte homeostasis contributes to white matter organization.