The protein complex formed by the Ca2+ sensor NCS-1 and the guanine exchange factor Ric8a co-regulates in a antagonistic manner synapse number and probability of neurotransmitter release, emerging as a potential therapeutic target for diseases affecting synapses such as Fragile X syndrome (FXS), the most common heritable autism disorder. By combining crystallographic and chemoinformatic methodologies, a new and small phenothiazine derivative has been found to inhibit this protein complex, whose contact surface is big and complex. The administration of the compound reduces the aberrant excess of synapse number to normal levels and improves associative learning in a Drosophila FXS model. Finally, the structure-function studies have demonstrated the mechanism of action of this new molecule. This work opens the path to the generation of new drugs to treat neuronal diseases affecting synapse function, such as Autism or Alzheimer.

This work has been carried out by researchers from three CSIC Institutes (Instituto de Química-Física “Rocasolano”, Instituto Cajal and Centro de Investigaciones Biológicas) and the BSRC “Alexander Fleming” in Greece.

Alicia Mansilla, Antonio Chaves-Sanjuan, Nuria E. Campillo, Ourania Semelidou, Loreto Martínez-González, Lourdes Infantes, Juana María González-Rubio, Carmen Gil, Santiago Conde, Efthimio M. C. Skoulaki, Alberto Ferrús, Ana Martínez, María José Sánchez-Barrena. “Interference of the complex between NCS-1 and Ric8a with phenothiazines regulates synaptic function and is an approach for fragile X syndrome”. Proc. Nat. Acad. Sci., PNAS (2017).
doi:10.1073/pnas.1611089114
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