Grey matter degeneration during multiple sclerosis is linked to activation of neuronal necroptosis by oxidized...

Oxidized phosphatidylcholines (OxPCs) are biomarkers of oxidative stress found in grey matter (GM) lesions during multiple sclerosis (MS), yet their distinct role in GM neurodegeneration remains undefined. Here we report that stereotaxic OxPC deposition in the mouse spinal cord GM induces age dependent neuroinflammation and neurodegeneration. Microglia are the predominant macrophages responding to OxPC induced GM lesions and help to mitigate acute neurodegeneration. Neuronal necroptosis activation in mouse GM lesions and neuronal upregulation of OxPCs and necroptosis activation in MS GM lesions suggest OxPC induced necroptosis promote GM degeneration during MS. In support, necroptosis inhibition ameliorates OxPC induced GM neuron loss. Finally, iron(ii)-containing heme deposition in the GM induces both OxPC formation and neuronal necroptosis activation, suggesting an endogenous upstream mechanism for generating neurotoxic OxPCs. These results highlight a plausible link between heme deposition, lipid peroxidation, and neuronal loss, and that necroptosis inhibition could help prevent GM neurodegeneration during MS.