Autoimmune neuroinflammation leads to neuronal death via MIF nuclease-mediated parthanatos.

Central nervous system inflammation is implicated in neurodegeneration across several disorders, including multiple sclerosis (MS). While marked therapeutic progress has been made in preventing relapses in MS, primary neuroprotection in this disease remains elusive. This, in part, is due to an incomplete understanding of the molecular pathways involved in immune-mediated neuronal death. Here we show that parthanatos, a recently described caspase-independent and DNA damage-induced cell death program, contributes to neuron death in the experimental autoimmune encephalomyelitis (EAE) mouse model of autoimmune neuroinflammation. We reveal that DNA damage increases in neurons during EAE, and that neurons are progressively lost over the disease course. Neurons in affected areas display intracellular hallmarks of the parthanatos cascade. Genetic or pharmacologic blockade of the final step in parthanatos, genomic fragmentation by macrophage migration inhibitory factor (MIF) nuclease, reduces neuron loss and disease severity. Transcriptomic characterization of neurons with and without MIF nuclease activity reveals parthanatos-dependent differences in response to EAE. Together, this work establishes parthanatos as a key mechanism of neuron cell death during neuroinflammation.