Neuroserpin is one of the serpins (serin protease inhibitors), a conserved superfamily of proteins that inhibit serin proteases by a mechanism that requires a high structural flexibility, and which renders serpin proteins very sensitive to point mutations that alter their folding and cellular handling. This molecular mechanism is at the base of a class of pathologies called the serpinopathies, which are due to mutations that cause serpin polymerisation and retention within the endoplasmic reticulum of the cell of synthesis. Six different polymerisation-causing mutations have been found in neuroserpin, a secreted serpin mainly expressed by neurons, as the cause of a rare but deadly type of dementia called FENIB. Although the pathological manifestations of serpin polymerisation depend on the inhibitory target and place of action of each specific serpin, the molecular mechanism is common and several aspects remain obscure for all serpinopathies. Particularly, little is known about the cell toxicity effects of polymer accumulation inside the endoplasmic reticulum. We have recently created a neural expression system and performed a RNA sequencing comparison of control cells and cells expressing a severe pathological FENIB variant of NS. We have found that cells expressing polymerogenic NS overexpress several anti-oxidant genes and undergo apoptosis when the anti-oxidant defences are blocked. Our preliminary results also suggest an alteration of mitochondrial physiology. Here we propose to further characterise the involvement of oxidative stress and mitochondrial and cytoskeleton dynamics, focusing on several genes identified in our RNA sequencing of G392E NS cells, in the neuronal degeneration underlying the dementia FENIB.
