Single nuclei transcriptomics from lumbar spinal cord of EAE mice treated with MIF nuclease inhibitor PAANIB1

Central nervous system inflammation is implicated in neurodegeneration across several disorders, including multiple sclerosis (MS). While marked therapeutic progress has been made through the suppression of immune cell trafficking and function, primary neuroprotection in MS remains elusive. This, in part, is due to an incomplete understanding of the molecular signaling 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 revealed that DNA damage increases in neurons during EAE, and that neurons are progressively lost over the disease course. Neurons in affected areas display intercellular hallmarks of the parthanatos cascade. Genetic or pharmacologic blockade of the final step in parthanatos, genomic fragmentation by MIF nuclease, reduces neuron loss and disease severity. Transcriptomic characterization of these neurons reveals parthanatos-dependent differences in response to EAE. Together, this work establishes parthanatos as a key mechanism of neuron cell death during neuroinflammation.