RalA inhibitor UA-30 is an orally active, direct small-molecule inhibitor of Ras-related small GTPase RalA, suppresses RalA activation and modulates the ERK/FOXO3a signaling pathway, enhancing mitophagy and mitigating amyotrophic lateral sclerosis (ALS)-like pathology.
UA-30 inhibits FOXO3a degradation via the ubiquitin-proteasome pathway, enhances FOXO3a stability, and supported transcription of mitophagy-related genes, including Pink1 and Prkn.
UA-30 suppresses RalA/ERK signaling, reduces inhibitory FOXO3a phosphorylation and ubiquitination, and restores FOXO3a nuclear localization.
UA-30 not only increases PINK1 and Parkin expression, but also promotes mitochondrial recruitment and activation of the PINK1/Parkin mitophagy machinery.
UA-30 ameliorates mitochondrial dysfunction in the SOD1G93A model by enhancing mitophagy, mediated through the targeted suppression of the RalA/ERK/FOXO3a signaling pathway.
UA-30 does not affect RalA protein levels or RalA mRNA levels.
UA-30 dose-dependently reduces RalA-GTP levels in small G protein activation assay (G-LISA) in spinal cord of SOD1G93A mice.
UA-30 stabilizes FOXO3a protein by inhibiting the RalA/ERK/FOXO3a signaling axis.
UA-30 promotes PINK1/Parkin-mediated mitophagy-related processes and mitochondrial quality control in male SOD1G93A mice.
UA-30 attenuates motor neuron loss and neuroinflammation, reduced muscle damage and fibrosis in the gastrocnemius muscle in SOD1G93A mice.