SERPINA3/SerpinA3n: a novel promising therapeutic target in prion diseases

Prion diseases, also known as transmissible spongiform encephalopathies (TSEs), belong to a class of fatal neurodegenerative disorders characterized by vacuolation and neuronal loss in the brain paralleled by cognitive and motor impairments. The main pathological event at the basis of these disorders is the conformational conversion of the physiological cellular prion protein (PrPC) into the misfolded and pathological isoform, called PrPSc, which acts as a corruptive seed, initiating a chain-reaction of PrPC-misfolding and aggregation. So far, several studies have focused on the ability of small molecules to interfere with the conversion mechanism, by either binding and stabilizing PrPC or blocking PrPSc aggregation and accumulation. However, we are still quite far from finding a cure, thus new therapeutic strategies and targets are required. Mounting evidence suggests that in addition to gene coding for the PrP (PRNP) other genes may contribute to the genetic susceptibility of TSEs. Indeed, recently, several studies reported that SERPINA3 (also known as alpha-1-antichymotrypsin), and its orthologue in mouse SerpinA3n, are strongly up-regulated in different model of prion diseases, both at mRNA and protein level. Moreover, increased overexpression of this serpin it is found in prion-infected human specimen, suggesting its possible involvement in the pathogenesis and progression of these disorders. Since serpins are serine protease inhibitors, we hypothesized that SERPINA3/SerpinA3n are involved in prion progression via inhibition of the protease, or the proteases, involved in prions clearance. Thus, given that all of the PrP- targeted therapeutic strategies developed until now have not been successful in the clinical practice, one of the aims of the thesis is to propose a novel drug strategy to clear prions interfering neither with PrPC nor with PrPSc. Therefore, we decided to test, in models of prion diseases, the activity of anti-SERPINA3 small molecules to evaluate possible changes in prion accumulation. Moreover, we have investigated how this serine protease inhibitor is upregulated during prion infection, focusing on the signaling cascade involved in this process. In the second part of the PhD project, we tried to identify pathways correlating prion accumulation and SERPINA3/SerpinA3n upregulation, with a special focus on the role of the JAK/STAT3 pathway.