Dottorato in BIOLOGIA CELLULARE E DELLO SVILUPPO

Titolo della tesi: Cellular and molecular basis of neuroserpin polymer formation and toxicity underlying neurodegeneration in FENIB

In this work we studied the cellular and molecular bases of familial encephalopathy with neuroserpin inclusion bodies (FENIB), a rare neurodegenerative disease caused by the accumulation of mutant neuroserpin (NS) polymers within neurons (Davis 1999). We investigated three different aspects of FENIB using cellular and structural biology approaches. In the first part, the research explored the neuronal alterations underlying neurodegeneration, and we found that mitochondrial dysfunction, oxidative stress, and metabolic alterations were induced by expression of the polymerogenic G392E variant of NS. In the second part, thanks to our national and international collaborations, we investigated the structure of NS polymers and the molecular mechanisms that drive the polymer formation utilizing electron microscopy and structural biology techniques. In the third part, we established a pipeline to identify and characterise novel variants of NS that may cause FENIB, through bioinformatic analyses and in vitro expression studies, paving the way for a faster diagnosis of FENIB.