Scientists from the IQFR report in Nature Communications a multidisciplinar and collaborative study that shows at molecular level an innovative strategy to improve synapse function in neurodegenerative diseases

Synapse function regulation depends on the correct interaction between the Ca2+ sensor NCS-1 and the guanine exchange factor Ric8a. Therefore, the interface of this protein-protein complex is a target for the design of therapeutic molecules that may constitute an innovative treatment for synaptopathies, a group of neuronal diseases where synapse number is disregulated. Previously, we published in PNAS how the inhibition of the NCS-1/Ric8a complex with a small phenothiazine reduces the abnormally high synapse number and enhances associative learning in a FXS animal model. This new work, product of a colaborative and multidisciplinar study done by researchers from IQFR, CIB, IRYCIS and UCM, has revealed that the stabilization of the protein complex with an acylhydrazone produces the opposite effect, re-stablishes synapse number and improves neuronal function in an Alzheimer´s disease model. The crystal structure of NCS-1 in complex with the bioactive molecule explains its mechanism of action at atomic level and suggests how to improve the eficacy of these regulatory molecules.


Canal-Martín A, Sastre J, Sánchez-Barrena MJ*, Canales A, Baldominos S, Pascual N, Martínez-González L, Molero D, Fernández-Valle ME, Sáez E, Blanco-Gabella P, Gómez-Rubio E, Martín-Santamaría S, Sáiz A, Mansilla A*, Cañada FJ, Jiménez-Barbero J, Martínez A, Pérez-Fernández R* (2019) Insights into Real-Time Chemical Processes in a Calcium Sensor Protein-Directed Dynamic Library. Nature Communications 10, article number: 2798. DOI: 10.1038/s41467-019-10627-w.