Modulation of the unfolded protein response with a C-terminal fragment of MANF facilitates recovery in models of multiple sclerosis

Inflammation in multiple sclerosis leads to chronic activation of a cellular stress mechanism, the unfolded protein response (UPR), which is thought to both exacerbate neuroinflammation and prevent regenerative tissue responses such as remyelination. The UPR-modulating protein MANF has shown great promise for attenuating chronic UPR activation and enhancing tissue regeneration in various disease models but does not reach the CNS when given peripherally. We utilized C-MANF, a C-terminal fragment of MANF, and showed that subcutaneous administration of C-MANF promoted motor function recovery and tissue regeneration in a mouse model of autoimmune demyelination. We demonstrated that C-MANF suppresses neuroinflammatory activation and facilitates the recovery of oligodendrocytes after demyelination, while reducing long-term activation of the UPR. Furthermore, we showed that C-MANF enhances myelination of primary OPCs in culture, that promotion of remyelination in cerebellar organotypic slice cultures is dependent on UPR-modulation, and that exogenously applied C-MANF suppresses chronic activation of all three UPR pathways in oligodendroglia. Finally, we showed that demyelination in MANF-deficient brains leads to extensive neuroinflammation and CNS degeneration, implicating UPR-modulation by MANF as a key component in tissue responses to demyelination. Altogether, we show that UPR modulation with C-MANF is a promising new therapeutic approach for treating neuroinflammatory demyelination. Autoimmune neuroinflammation in diseases such as multiple sclerosis (MS) induces activation of a stress pathway called the unfolded protein response (UPR) in demyelinated lesions, preventing remyelination. C-MANF, a novel protein fragment, enhanced lesion regeneration after subcutaneous injection by inhibiting chronic UPR activation. This reduced neuroinflammation and enhanced remyelination.