Neuroscience

The dementia FENIB is a rare but fatal neurodegenerative condition due to point mutations in the neuronal protein neuroserpin (NS). NS is one of the serpins (serin protease inhibitors), a conserved superfamily of proteins that inhibit serin proteases by a mechanism that requires high structural flexibility, rendering serpin proteins very sensitive to point mutations that alter their folding and promote their intracellular polymerisation and accumulation within the endoplasmic reticulum of the cell. This constitutes the molecular mechanism underlying the serpinopathies. 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 due to polymer accumulation in 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 variant of NS. We have found that cells expressing polymerogenic NS upregulate several anti-oxidant genes and undergo apoptosis when the anti-oxidant defences are blocked. Our preliminary results also indicate an alteration of mitochondrial physiology in these cells. Here we propose to characterise the nature of the ER stress caused by accumulation of NS polymers in neurons and to investigate the mitochondrial alterations in cells expressing mutant NS, particularly in connexion with oxidative stress, ER-mitochondrial interaction and Ca2+ signalling, and their role in the neuronal degeneration underlying the dementia FENIB.