Neuroserpin misfolding and FENIB neurodegeneration: mechanism and inhibition processes

Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a genetic disease characterized by progressive neurodegeneration and dementia. FENIB is caused by mutations in the protein called neuroserpin (NS). These mutations lead to NS polymerization and accumulation within neurons. To date, the lack of a cure for FENIB is mainly due to I) incomplete understanding of the structure and formation of NS polymers, II) poor knowledge of polymer toxicity mechanisms and III) lack of appropriate inhibitors of NS polymerization. In recent years we have already worked on various structural and biophysical aspects of NS polymers formation. Recently, we have also identified embelin (EMB) as the first (and the only) molecule able to inhibit the formation of NS polymers and to cause the dissolution of polymers in vitro. Recent data indicate that N-glycosylation (a chemical modification of proteins performed by human cells) plays a key role in NS polymerization. So far, non-glycosylated NS has been the standard for biochemical analyses; thus, we are working to create a glycosylated NS production system (gNS). We plan to perform biochemical and biophysical studies of gNS and to use gNS for a new series of polymerization tests in search of new inhibitors. In addition, we will perform a systematic approach to chemically modify EMB and in parallel, we will identify the binding site between gNS and EMB and we will develop further modifications of EMB to obtain increasingly effective polymerization inhibitors. Finally the most promising inhibitors will be tested in cellular and murine FENIB models. Taken together, these activities define the main purpose of this project: a rational research and production of synthetic NS polymerization inhibitors that are active in vitro and in vivo.