Other types of cell death may be critical in regulating OL death but have not yet been demonstrably shown to do so in human demyelinating disease. Experimental OL death and demyelination induced by the copper chelator cuprizone involves ferroptosis70—an iron-dependent form of cell death induced by perturbations of the intracellular environment, leading to lipid peroxidation under conditions of glutathione deficiency. This likely reflects an impact on OL metabolism, as copper-containing iron-oxidizing enzymes (ferroxidases) are involved in mitigating oxidative stress. Indeed, OL loss in the cuprizone model can be rescued by treatment with a lipid radical scavenging molecule, ferrostatin 170. Overall, the mechanisms by which human OLs undergo cell death are still being resolved, with the potential for new regulated cell death mechanisms to be uncovered and the development of novel therapeutic interventions. Whether these distinct forms of cell death related to distinct pathologies, CNS regions, age, or subpopulations of OLs remains to be defined.
