ASYN and tau interaction : new drug target for neurodegenerative diseases

Tese de doutoramento, Bioquímica (Biotecnologia), Universidade de Lisboa, Faculdade de Ciências, 2014

Neurodegenerative diseases are among the most complex and puzzling human disorders and in the last century the number of people affected by neurodegenerative disorders is increasing year after year. These devastating disorders currently do not have any effective therapies or treatments, thus are a social and economic burden for modern society and novel therapeutic strategies need to be developed for these disease states. Synucleinopathies and tauopathies regroup a wide number of neurodegenerative disorders characterized by the presence of abnormal protein aggregates respectively composed of alpha-synuclein (ASYN) or tau protein. Several reports revealed a consisting overlapping between these two groups of disorders and that the interactions between ASYN and tau may be a relevant disease component that enhances the pathological cascade and spreads the neuronal damage. Budding yeast have been largely used to perform studies on the physiopathology of synucleopathies and tauopathies and are a powerful tool for rapid screening assays that have resulted in the identification of several promising therapeutic drugs and targets. In this work we used yeast as a model system to reproduce the synergistic cytotoxic effect mediated by the co-expression of the human ASYN and tau proteins that recapitulates some of the pathological features observed in patient’s brain. The model was used to perform genome-wide screening and high-throughput assays to identify both genes and natural extracts able to modulate the synergistic cytotoxic interactions of ASYN and tau. In the end, we were able to identify 5 different S. cerevisiae genomic fragments containing a total of 25 different complete genes and 11 natural extracts able to interfere with the reported synergistic cytotoxicity. These modulators have the potential to be further explored in other appropriate disease models and might be relevant for academic groups and companies working on neurodegeneration engaged in drug discovery.

Fundação para a Ciência e a Tecnologia (FCT); European Comission