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(-)- Gossypol Inhibition of Musashi-Mediated Forgetting Improves Memory and Age-Dependent Memory Decline in
Pavlina Mastrandreas1,2,3, Andreas Arnold4,5,6, Csaba Boglari4,5,6
1Transfaculty Research Platform Molecular and Cognitive Neurosciences, University of Basel, Birmannsgasse 8, 4055, Basel, Switzerland. pavlina.mastrandreas@unibas.ch.
Abstract:
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.
Insights
Pharmacological inhibition of Musashi proteins (MSIs) enhances memory retention and reverses age-related memory decline. This suggests targeting MSIs could be a novel strategy for memory modulation.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Musashi RNA-binding proteins (MSIs) are crucial for stem cell maintenance, tumorigenesis, and nervous system development.
- MSI-1 in C. elegans regulates associative learning and memory forgetting by controlling the translation of the Arp2/3 actin branching complex.
- The conserved role of MSI proteins in memory warrants investigation into their pharmacological modulation.
Purpose of the Study:
- To investigate the evolutionary conserved role of Musashi proteins in memory.
- To determine the effect of pharmacological inhibition of Musashi proteins on memory retention.
- To explore the potential of Musashi inhibition as a therapeutic strategy for memory enhancement, including in aged individuals.
Main Methods:
- Expression of human Musashi 1 (MSI1) and Musashi 2 (MSI2) in msi-1(lf) C. elegans to assess functional rescue.
- Pharmacological inhibition of MSI1 and MSI2 using (-)-gossypol in wild-type and mutant worms.
- Assessment of memory retention, locomotor activity, chemotaxis, and learning abilities following drug treatment.
- Western blotting and confocal microscopy to analyze MSI-1 protein levels and localization post-treatment.
- Specific neuronal expression of human MSI1 in AVA neurons to investigate drug effects within a memory circuit.
- Treatment of aged worms with (-)-gossypol to evaluate its impact on age-dependent memory decline.
Main Results:
- Human MSI1 and MSI2 fully rescued the memory-related phenotype of msi-1(lf) worms, confirming their conserved function.
- Pharmacological inhibition of MSI1 and MSI2 with (-)-gossypol significantly improved memory retention in wild-type worms.
- No significant deficits in locomotion, chemotaxis, or learning were observed in treated worms.
- (-)-Gossypol did not affect MSI-1 protein abundance, indicating post-translational inhibition.
- The drug suppressed the rescue effect of human MSI1 in AVA neurons, demonstrating pathway regulation in a specific neural circuit.
- Treatment with (-)-gossypol reversed age-dependent memory decline in aged worms.
Conclusions:
- Musashi proteins play a conserved role in memory modulation across species.
- Pharmacological inhibition of Musashi activity using (-)-gossypol enhances memory retention and reverses age-related memory decline.
- Post-translational inhibition of Musashi by (-)-gossypol is effective and does not impair basic behaviors or learning.
- Targeting Musashi proteins represents a promising therapeutic avenue for memory enhancement and combating cognitive decline.
