Polysialylation at early stages of oligodendrocyte differentiation promotes myelin repair

Abstract

Polysialic acid is a glycan modification of the neural cell adhesion molecule (NCAM) produced by the polysialyltransferases ST8SIA2 and ST8SIA4. Polysialic acid has been detected in multiple sclerosis plaques, but its beneficial or adverse role in remyelination is elusive. Here, we show that, despite a developmental delay, myelination at the onset and during cuprizone-induced demyelination was unaffected in male Ncam1- / - or St8sia2- / - mice. However, remyelination, restoration of oligodendrocyte densities, and motor recovery after the cessation of cuprizone treatment were compromised. Impaired differentiation of NCAM- or ST8SIA2-negative oligodendrocyte precursors suggested an underlying cell-autonomous mechanism. In contrast, premature differentiation in ST8SIA4-negative cultures explained the accelerated remyelination previously observed in St8sia4- / - mice. mRNA profiling during differentiation of human stem cell-derived and primary murine oligodendrocytes indicated that the opposing roles of ST8SIA2 and ST8SIA4 arise from sequential expression. We also provide evidence that potentiation of ST8SIA2 by 9-cis-retinoic acid and artificial polysialylation of oligodendrocyte precursors by a bacterial polysialyltransferase are mechanisms to promote oligodendrocytic differentiation. Thus, differential targeting of polysialyltransferases and polysialic acid engineering are promising strategies to advance the treatment of demyelinating diseases.