SERPINA3/SerpinA3n role in prion diseases

Prion diseases are a family of rare and fatal neurodegenerative disorders, characterized by the accumulation of abnormally folded prion protein. Previous data suggested that SERPINA3/SerpinA3n might be involved in the pathogenesis and the progression of prion diseases. Serpins represent the most broadly distributed superfamily of proteases inhibitors. They contribute to a variety of physiological functions and any alterations of the serpin-protease equilibrium can lead to pathological consequences. Besides prion diseases, SERPINA3 dysregulation has been associated with other neurodegenerative disorders, such as Alzheimer’s disease. The hypothesis supporting SERPINA3/SerpinA3n involvement in prion diseases could reside in its upregulation upon prion inoculation, which will be responsible to a decrease activity of the protease(s) involved in the clearance of the pathological prion aggregates. The differential expression of other serpin superfamily members has been investigated in human frontal cortex samples of sporadic cases of Creutzfeldt-Jakob disease and in an animal models of prion disease. Besides the already observed SERPINA3 upregulation, SERPINB1, SERPINE1, SERPINB6, SERPING1, SERPINH1 and SERPINI1 were dysregulated in prion-infected individuals compared to age-matched controls. Together with the previously known SerpinA3n increased expression, prion-infected mice showed the upregulation of SerpinF2. Therefore, among the differentially regulated serpins, SERPINA3/SerpinA3n is the only member highly dysregulated in both prion-infected human and murine samples, suggesting its potential role in diseases progression. SerpinA3n protein and transcript expression has been confirmed in chronically prion-infected immortalized cells. Interestingly, slight changes in prion levels have been observed upon SerpinA3n modulation in infected cells. Finally, prion inoculation of SerpinA3n depleted mice has been performed to observe their survival and incubation period compared to prion inoculated wild type mice. Although no differences have been observed between transgenic and wild-type mice, possible compensatory effects given by the upregulation of another serpins’ member, SerpinI1, would explain the unaltered prion clearance. However, these results suggest SERPINA3/SerpinA3n as a novel potential therapeutic target, opening the way for future therapies aimed to boost the clearance of protein aggregates responsible for prion and other neurodegenerative diseases.