Development of a yeast model to investigate the molecular aspects involved in the neurodegenerative disease FENIB

Thanks to its significant evolutionary conservation of eukaryotic biochemical pathways, the yeast Saccharomyces cerevisiae has been employed as a model organism in order to study and unravel the basis of a wide variety of human cellular processes, such as neuronal proteotoxic stress and its implication in cell ageing and death [1]. Thus, our purpose is to use yeast as a model to study a neurodegenerative autosomal dominant disorder called FENIB (Familial Encephalopathy with Neuroserpin Inclusion Bodies). FENIB is a rare conformational disease caused by the aberrant folding of neuroserpin: different mutations in its coding sequence (NS1) induce the polymerization of the protein and its subsequent intracellular deposition, which promotes proteotoxic stress. Severity and age of onset of the symptoms – such as dementia, epilepsy, convulsions and tremor - depend on the specific mutation. Even though different cellular and organism models have been used, no cure has been discovered yet [2]: for this reason, our research group is working on the development and implementation of S. cereviasiae as a new FENIB cellular model, therefore validating yeast as an efficient tool to study neurodegenerative disorders. Through the identification of the molecular mechanisms and the pathways involved, a humanized yeast model could allow a better understanding of the disease onset, progression and cytotoxicity-induced, finding out new possible therapeutic targets. References: [1] Fruhmann, G et al.,. (2017) Yeast buddies helping to unravel the complexity of neurodegenerative disorders. Mech Ageing Dev. Jan;161(Pt B):288-305. [2] Guadagno, NA et al., (2017) Neuroserpin polymers cause oxidative stress in a neuronal model of the dementia FENIB. Neurobiology of Disease, 103:32-44