Dottorato in BIOLOGIA CELLULARE E DELLO SVILUPPO

Titolo della tesi: Yeast as a tool to unveil the cellular and molecular mechanisms underlying neurodegeneration in dementia FENIB

The budding yeast Saccharomyces cerevisiae has been extensively used as a model system for understanding eukaryotic cellular processes. It is an established model organism for the analysis of evolutionarily conserved cellular pathways relevant for protein degradation, protein quality control systems, cell death and aging. In this context S. cerevisiae is an excellent candidate for studying neuropathies, such as FENIB (Familial Encephalopathy with Neuroserpin Inclusion Bodies), a rare neurodegenerative disorder with autosomal dominant inheritance. The dementia FENIB is caused by different mutations in neuroserpin (NS) gene that promote NS polymerization and its subsequent intracellular deposition, leading to a poorly understood cell toxicity. The severity of the disease phenotype depends on the specific mutation. We focused on studying one of the most severe forms of FENIB, due to the substitution of the glycine at position 392 with glutamic acid (G392E). To create a humanized yeast model for FENIB, the wild-type and the mutant variant (G392E) of the NS gene were cloned into yeast expression vectors and inserted in different yeast strains. In this study we reported data on NS expression and localization within the yeast cells. Moreover, we analysed the cytotoxic effect of NS with the aim to identify the molecular mechanisms underlying toxicity.