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Published on: September 21, 2021
Natural product screening reveals nanomolar Musashi2 inhibitor reducing forgetting in Caenorhabditis elegans
Tamara Balsiger1, Robert Hagmann1, Kim-Dung Huynh2
1Division of Pharmaceutical Biology, Department of Pharmaceutical Sciences, University of Basel, Basel 4056, Switzerland.
Abstract:
Physiological forgetting is an essential process for normal brain function, yet the molecular mechanisms underlying memory loss, including pathologically accelerated forms, are still not fully elucidated. A key mechanism to induce forgetting was identified in Caenorhabditis elegans (C. elegans) involving the RNA-binding protein Musashi (MSI), which acts as a translational regulator. Here, we report the discovery of a series of nanomolar inhibitors of MSI identified via a high-throughput natural product screening platform of a plant extract library. Ellagic acid (EA) emerged as one of the most potent inhibitors, improving both short- and long-term associative memory in an all-or-none like manner in an in vivo C. elegans memory model. Notably, EA had no effect in msi loss-of-function mutant worms, corroborating MSI as its molecular target. These findings underscore MSI as a therapeutic target for modulating forgetting and establish EA as a nanomolar MSI inhibitor and promising lead compound for mitigating memory decay.
Insights
Researchers discovered natural compounds that inhibit Musashi (MSI), a protein linked to forgetting. Ellagic acid (EA) improved memory in C. elegans, showing potential for treating memory loss.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Physiological forgetting is crucial for brain function, but its molecular basis, especially in accelerated memory loss, remains unclear.
- The RNA-binding protein Musashi (MSI) acts as a translational regulator and is implicated in inducing forgetting in C. elegans.
- Identifying molecular targets and inhibitors is key to understanding and potentially treating memory decay.
Purpose of the Study:
- To discover novel inhibitors of the Musashi (MSI) protein.
- To evaluate the therapeutic potential of identified inhibitors in a C. elegans memory model.
- To establish MSI as a druggable target for modulating memory processes.
Main Methods:
- High-throughput screening of a plant extract library to identify MSI inhibitors.
- Utilizing an in vivo C. elegans associative memory assay to test inhibitor efficacy.
- Employing loss-of-function mutants to confirm the molecular target of identified compounds.
Main Results:
- A series of nanomolar MSI inhibitors were discovered from natural products.
- Ellagic acid (EA) was identified as a potent MSI inhibitor, significantly improving short- and long-term associative memory in C. elegans.
- EA's memory-enhancing effects were dependent on MSI, confirming it as the molecular target.
Conclusions:
- Musashi (MSI) is a viable therapeutic target for controlling forgetting and memory decay.
- Ellagic acid (EA) is a promising lead compound with nanomolar inhibitory activity against MSI, demonstrating potential for memory enhancement applications.
