Ricerc@Sapienza

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 underlies a class of pathologies called the serpinopathies, where point mutations 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 published a novel neural expression system, in which RNA sequencing has uncovered the overexpression of several anti-oxidant genes in cells expressing the highly polymerogenic FENIB G392E variant of NS. These cells undergo apoptosis when the anti-oxidant defences are inhibited pharmacologically, and our recent results show alterations in mitochondrial distribution across G392E NS neurons. This phenotype is worsened by a chelator of the antioxidant molecule glutathione, supporting a link between oxidative stress and mitochondrial dysfunction in the neurodegeneration FENIB. This proposal aims to continue our studies on mitochondrial alterations and their relationship with the endoplasmic reticulum where polymers of G392E NS accumulate, inducing a stress response that is still poorly understood.