Gilstrap, E. | bioRxiv Science

bioRxiv2025

Validating FOXO4 as a therapeutic target for protecting against ischemia-reperfusion-caused neuronal injury

Previous data suggest that FOXO4 facilitates inflammation and oxidative stress in non-brain tissues under stress or disease conditions, indicating that blocking FOXO4 function may be neuroprotective in ischemia-reperfusion-induced brain injury. However, this possibility has not been tested in a cerebral ischemia-reperfusion condition. Here, we treated the FOXO4 knockout (KO) primary neuronal cultures with oxidative stress or oxygen-glucose deprivation (OGD) or subjected the KO mice to the transient middle cerebral artery occlusion (tMCAO). Our results showed that KO of FOXO4 reduced oxidative stress and OGD-induced neuronal death, attenuated tMCAO-caused infarct volume, improved animal survival, decreased neurological deficits, and enhanced functional recovery compared to the WT cells or mice. Immunohistochemical staining and Western blot analysis suggested decreased neuroinflammation in the KO brain. These data indicate that FOXO4 is a therapeutic target, and disrupting its activity promotes neuronal survival following ischemic stroke-induced brain injury.

neuroscience↗

bioRxiv2024

Impaired proteasome induces mitochondrial DNA release to activate the cGAS-STING signaling pathway and cause necroptosis in mouse brain

Impaired proteasome function is consistently associated with many neurodegenerative disorders, including Alzheimers disease (AD), showing neuroinflammation and neurodegeneration; however, how impaired proteasome causes neuroinflammation and neuronal death remains less understood. Here, we studied the effect of impaired proteasome on neuroinflammation and neuronal death in a knockout (KO) mouse model with reduced proteasome activity in the brain. We discovered that impaired proteasome led to the release of mitochondrial dsDNA into the cytosol, activating the cGAS-STING signaling pathway, and upregulating pro-inflammatory cytokines in the KO mouse brain relative to the control brain. Importantly, we also observed reduced brain weight, elevation of the mixed lineage kinase domain-like (MLKL) protein, phosphorylated MLKL, and receptor-interactive protein kinases (RIPK) 1 and 3 in the KO mouse brain compared to the control brain, suggesting activation of necroptosis in the KO brains. These data indicate that impaired proteasome activates the cGAS-STING pathway to induce neuroinflammation and neurodegeneration via a necroptotic manner. Our results suggest that neuroinflammation and necroptosis may be generalized factors caused by reduced proteasome activity observed in diverse neurodegenerative disorders.

neuroscience↗