Neuroserpin (NS) 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 underlies a class of pathologies called the serpinopathies, where point mutations cause serpin polymerisation and retention within the endoplasmic reticulum (ER). To date, six different mutations have been described in NS, a secreted serpin expressed mainly by neurons, which cause polymer formation and a rare but deadly type of neurodegenerative 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 cellular toxicity effects of polymer accumulation inside the ER. We have recently published our neuronal cell model of FENIB and described for the first time an oxidative stress response in cells expressing the highly polymerogenic G392E variant of NS. These cells undergo apoptosis when the antioxidant defences are inhibited pharmacologically, and our recent results show alterations in mitochondrial distribution in G392E NS neurons. This phenotype is worsened by a chelator of the antioxidant molecule glutathione and ameliorated by antioxidant molecules, and is associated to a reduction in ER-mitochondria contact sites and alterations in neuronal morphology, supporting a link between oxidative stress, mitochondrial dysfunction and cytoskeletal alterations in the neurodegeneration FENIB. This proposal is thus a continuation of our studies on the cellular alterations, with a novel focus on cytoskeletal effects, caused by polymerogenic mutant NS and how they lead to neuronal death in FENIB.
