(-)- Gossypol Inhibition of Musashi-Mediated Forgetting Improves Memory and Age-Dependent Memory Decline in Caenorhabditis elegans

• Published in: Molecular neurobiology Vol. 60; no. 2; pp. 820 - 835
• Main Authors: Mastrandreas, Pavlina, Arnold, Andreas, Boglari, Csaba, de Quervain, Dominique J.-F., Stetak, Attila, Papassotiropoulos, Andreas
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-02-2023; Springer Nature B.V
• Subjects: 3' Untranslated regions; Actin; Aged; Animals; Associative learning; Biomedical and Life Sciences; Biomedicine; Caenorhabditis elegans - metabolism; Cell Biology; Confocal microscopy; Evolutionary conservation; Gene expression; Gossypol; Gossypol - metabolism; Gossypol - pharmacology; Humans; Memory Disorders - drug therapy; MSI-1 protein; Musashi protein; Nerve Tissue Proteins - metabolism; Nervous system; Neurobiology; Neurology; Neurons - metabolism; Neurosciences; Phenotypes; Post-translation; RNA-binding protein; RNA-Binding Proteins - metabolism; Stem cells; Stem Cells - metabolism; Tumorigenesis; Western blotting; Worms; Forgetting; Ageing; Musashi; (-)- Gossypol; C. elegans
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-022-03116-7

Musashi RNA-binding proteins (MSIs) retain a pivotal role in stem cell maintenance, tumorigenesis, and nervous system development. Recently, we showed in
C. elegans
that Musashi (MSI-1) actively promotes forgetting upon associative learning via a 3’UTR-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 Musashi 1 (MSI1) and Musashi 2 (MSI2) under the endogenous Musashi promoter fully rescued the phenotype of
msi-1(lf)
worms. Furthermore, pharmacological inhibition of human 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.