Williams, R. E. | Search bioRxiv

bioRxiv2026

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.

microbiology↗

bioRxiv2023

Roadmap for Canonical and Extended Endocannabinoid System Receptors in Peripheral Organs of Preclinical Animal Models

The endocannabinoid system is widely expressed throughout the body and is comprised of receptors, ligands, and enzymes that maintain metabolic, immune, and reproductive homeostasis. Increasing interest in the endocannabinoid system has arisen due to these physiologic roles, policy changes leading to more widespread recreational use, and the therapeutic potential of Cannabis and phytocannabinoids. Rodents have been the primary preclinical model of focus due to their relative low cost, short gestational period, genetic manipulation strategies, and gold-standard behavioral tests. However, the potential for lack of clinical translation to non-human primates and humans is high as cross-species comparisons of the endocannabinoid system has not been evaluated. To bridge this gap in knowledge, we evaluate the relative gene expression of 14 canonical and extended endocannabinoid receptors in seven peripheral organs of C57/BL6 mice, Sprague-Dawley rats, and non-human primate rhesus macaques. Notably, we identify species- and organ-specific heterogeneity in endocannabinoid receptor distribution where there is surprisingly limited overlap among the preclinical models. Importantly, we determined there were only five receptors (CB2, GPR18, GPR55, TRPV2, and FAAH) that had identical expression patterns in mice, rats, and rhesus macaques. Our findings demonstrate a critical, yet previously unappreciated, contributor to challenges of rigor and reproducibility in the cannabinoid field, which has profound implications in hampering progress in understanding the complexity of the endocannabinoid system and development of cannabinoid-based therapies.

molecular biology↗