Written by Dr. Hannah K Shorrock Edited by Dr. Hayley McLoughlin
A C. elegans model of SCA3 helps to identify the serotonin receptor agonist befiradol as a potential therapeutic for SCA3
To move toward treatments for ataxia patients, it is important to understand what cellular and molecular pathways are dysfunctional in the disease. We can then identify specific cellular or molecular targets that are suitable for therapeutic intervention. In this study, researchers built on their previous work that adjusting serotonergic signaling could be used as a treatment approach in SCA3. They did this by identifying two drugs that target different combinations of serotonin receptors. When used together, these two drugs provide therapeutic benefit in Caenorhabditis elegans (C. elegans) models of SCA3. This study moves us closer to therapies for SCA3 by identifying the parts of the serotonergic signaling pathway most suitable to be targeted for further drug development.
The research team had previously worked with a small molecule that targeted multiple cellular pathways. This included many components of the serotonergic signaling pathway. In this study, the group wanted to identify the aspects of this signaling pathway responsible for the therapeutic benefit seen with these treatments. They used a C. elegans animal model of SCA3 in which a form of the SCA3 causing gene, ATXN3, containing 130 CAG repeats is expressed in neurons.
C. elegans have four receptors within the serotonergic signaling pathway that are highly similar to four receptors in humans. This makes them a strong model system to explore the treatment potential of targeting these receptors. The mutant ATXN3 C. elegans move less and they move slower than C. elegans without the ATXN3 expansion.
The group studied the effect of two drugs targeting receptors involved in the serotonergic signaling pathway on these movement defects. They found that at the same concentration both tandospirone and befiradol treatment for four days improved the motor performance of mutant ATXN3 C. elegans. This occurred for both the speed and amount of movement. Importantly, neither of the drugs affected the motor performance of C. elegans without the mutant ATXN3. This indicates that in this model system, the effect of the treatments is specific to the presence of the repeat expansion mutation. This is a desirable quality for any therapeutic strategy for a repeat expansion disease.

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