Serpin function and disease: cellular toxicity of neuroserpin polymers and novel roles of alpha1-antitrypsin

The serpinopathies are due to misfolding and intracellular polymerisation of mutant serpin variants within the endoplasmic reticulum of the cell of synthesis and can be classified as conformational diseases, which arise when proteins undergo self-association and tissue deposition (Carrell and Lomas, 1997). Examples of human mutant serpins accumulating and causing a toxic gain of function are alpha1 antitrypsin variants underlying liver cirrhosis and mutants of neuroserpin causing the dementia familial encephalopathy with neuroserpin inclusion bodies (FENIB) (Roussel et al., 2011). Here we investigate with diverse approaches very different aspects of both pathologies. In the case of FENIB, following previous work in our laboratory in which we demonstrated the presence of oxidative stress in a novel neuronal model for FENIB neurodegeneration (Guadagno et al., 2017), we concentrate on cellular aspects of neuroserpin polymer toxicity, describing alterations in the morphology and function of the mitochondrial network and their interconnection with oxidative stress and changes in the communication between ER and mitochondria. Regarding alpha1 antitrypsin deficiency, we present the development and characterisation of functional monoclonal antibodies to explore the immunomodulatory roles of this protein.