Encephalitic Alphavirus Infection Induces PARP-1 Hyperactivation Mediated Energy Collapse in Motor Neurons

Motor neurons are highly vulnerable to metabolic stress, yet the mechanisms driving their degeneration during neurotropic alphavirus infections remain unclear. Venezuelan equine encephalitis virus (VEEV) causes motor neuron injury, but the intrinsic pathways underlying this susceptibility are not fully defined. Previous work suggests alphavirus-infected motor neurons may die through caspase-independent mechanisms. Here, we show that VEEV infection induces sustained activation of the DNA repair enzyme poly(ADP-ribose) polymerase-1 (PARP-1), leading to depletion of NAD ⁺ and ATP in murine NSC34 motor neuron-like cells and human iPSC-derived motor neurons. These metabolic changes precede mitochondrial depolarization and cell death. Pharmacological inhibition or genetic reduction of PARP-1 partially restores NAD ⁺ and ATP and improves cell survival, indicating that PARP-1 hyperactivation directly contributes to energetic collapse and intrinsic motor neuron death. These results identify PARP-1 as a key driver of energy failure during VEEV infection and a potential target to limit neuronal injury in neurotropic viral infections.