Kucera, A. | bioRxiv Science

bioRxiv2026

Premyelinating Oligodendrocyte Survival Governs CNS Remyelination

Myelinating oligodendrocytes are produced throughout life by the constitutive differentiation of oligodendrocyte precursor cells (OPCs). However, the rate of oligodendrocyte generation changes with age and after a demyelinating injury. Here, we report that variation in premyelinating oligodendrocyte (preOL) survival modulates the rate of oligodendrocyte production. PreOL survival increased to drive the regeneration of oligodendrocytes after demyelination and decreased in middle-aged mice to contribute to age-related decline in oligodendrocyte production. Furthermore, we demonstrate that treatment with a GPR17 antagonist, Myro-02, increases oligodendrocyte replacement by promoting preOL survival after demyelination. Together, our findings demonstrate that increased survival of preOLs governs the regeneration of oligodendrocytes following demyelinating injury and suggest that modulating preOL survival may be an alternative therapeutic avenue to promote oligodendrocyte regeneration.

neuroscience↗

bioRxiv2020

Invariant chain with an AP3 interacting sorting signal is sorted to late endosomal compartments and may improve MHC class I loading and presentation.

Invariant chain (Ii) is traditionally known as the dedicated MHCII chaperone. Recent reports have broadened our understanding about various tasks that Ii plays including its physiological role in MHCI cross-presentation. Ii bound MHCI via the MHCII scaffolding CLIP peptide may facilitate MHCI trafficking to the endosomal pathway. The sorting function of Ii depends on two leucine-based sorting signals present in the cytoplasmic tail that acts as binding sites for the adaptor proteins AP-1/AP-2. Here we increased the Ii cross-presentation potency by replacing these with an AP3 motif resulting an efficient transport of Ii from TGN to late endosomes. We also replaced the CLIP region of li with a therapeutically relevant peptide, MART-1. We found the Ii AP3mutant-MART1 construct was capable of loading MHCI and stimulate specific T-cell response more efficiently than the wild type counterpart. The results show that Ii with an AP3 binding sorting motif carrying peptide epitope(s) can promote efficient antigen presentation to cytotoxic T cells (CTLs) independent of the ER located classical MHCI peptide loading machinery.

immunology↗