Aboelnour, E. L.; Vanoverbeke, V. R.; Hatfield, M. M.; Adams, K. L.

Demyelinating diseases, such as Multiple Sclerosis (MS), are debilitating conditions characterized by loss of the myelin sheaths, ultimately leading to neurodegeneration. Toxicity models are among the most commonly used mouse models to induce demyelination; however, it remains unclear whether different demyelination models elicit distinct glial responses, and how comparable these changes are to MS. To address this gap, we integrated new and published single cell transcriptomic data of the subcortical white matter from lysophosphatidylcholine (LPC) and cuprizone toxicity models, and compared them to an existing human MS dataset. We find that LPC and cuprizone treatments induce distinct oligodendrocyte (OL) states, but a highly conserved microglial response upon demyelination. Interestingly, remyelinating OLs converge on an altered maturation state in both LPC and cuprizone models, potentially due to persistent activation of microglia at remyelination stages. Comparison of the mouse models with MS tissue reveals that key OL gene signatures specific to LPC and cuprizone demyelination are observed in MS patients, while microglia appear more heterogeneous across the different types of MS lesions. Finally, cross-species analysis highlights a conserved phenotype shared between cuprizone and actively demyelinating MS lesions, with downregulation of genes required for stable myelin production and increased cellular stress pathways. Overall, this comparative analysis uncovers specific gene expression differences between mouse demyelination models and human MS lesions, providing a foundation for using the animal models effectively to advance remyelination therapies.