Neurotropic 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 IMPORTANCE: Venezuelan equine encephalitis virus (VEEV) is a mosquito-borne pathogen that causes debilitating neurological disease, often targeting motor neurons and leading to permanent injury. While VEEV is known to cause significant damage to these nerve cells, the intrinsic pathways driving this susceptibility are not fully defined. This study demonstrates that VEEV infection induces sustained activation of the DNA repair enzyme poly(ADP-ribose) polymerase-1 (PARP-1), which effectively drains the cell of essential NAD⁺ and ATP. This massive energy failure precedes mitochondrial depolarization and cell death. By showing that pharmacological inhibition or genetic reduction of PARP-1 partially restores energy levels and improves survival in both murine and human motor neurons, these results identify a key driver of cellular collapse. These findings suggest that targeting PARP-1 could provide a potential therapeutic strategy to limit neuronal injury during neurotropic viral infections of the central nervous system.