(-)-Gossypol inhibition of musashi-mediated forgetting improves memory and age-dependent memory decline in Caenorhabditis elegans

Abstract

Musashi RNA-binding proteins retain a pivotal role in stem cell maintenance, tumorigenesis, and nervous system development. Recently, we showed in C. elegans that MSI1 actively promotes forgetting upon associative learning via a 3UTR-dependent translational expression of the Arp2/3 actin branching complex. Here, we investigated the evolutionary conserved role of MSI proteins and the effect of their pharmacological inhibition on memory. Expression of human MSI1 and MSI2 under the endogenous musashi promoter fully rescued the phenotype of msi-1(lf) worms. Furthermore, pharmacological inhibition of MSI1 and MSI2 activity using (-)-gossypol resulted in improved memory retention, without causing locomotor, chemotactic, or learning deficits. No drug effect was observed in msi-1(lf) treated worms. Using Western blotting and confocal microscopy we found no changes in MSI-1 protein abundance following (-)-gossypol treatment, suggesting that musashi gene expression remains unaltered and that the compound exerts its inhibitory effect post-translationally. Additionally, (-)-gossypol suppressed the previously seen rescue of the msi-1(lf) phenotype in worms expressing human MSI1 specifically in the AVA neuron, indicating that (-)-gossypol can regulate the musashi pathway in a memory-related neuronal circuit in worms. Finally, treating aged worms with (-)-gossypol reversed physiological age-dependent memory decline. Taken together, our findings indicate that pharmacological inhibition of musashi might represent a promising approach for memory modulation.