The role of neuroserpin in Familial Encephalopathy with Neuroserpin Inclusion Bodies (FENIB)

Neuroserpin is a member of a large family of proteins collectively named serpins. Human neuroserpin (hNS) is present in the nervous system; its physiological functions are poorly understood, but it is known to play a key role in the connection between neurons, in memory and learning. Five hNS single amino acid mutations are responsible for a rare genetic disease, known as Familial Encephalopathy with Neuroserpin Inclusion Bodies (FENIB). The main symptoms of the disease are early onset dementia, epilepsy and problems in muscle control. FENIB is a fatal neurodegenerative disease that may show the early symptoms within the first decade of life; no cure is currently available. Mutated hNS is an unstable protein that associates into large polymeric aggregates accumulating inside the nervous cells. Research so far on mutations, formation of hNS polymers and the severity of the disease, highlight the genetic nature of FENIB. The molecular and cellular details of formation, transport and physio-pathological effects of the hNS polymers are far from being understood.Our network of four research units, located in Milano, Rome and Palermo, plans to fill such gap in knowledge addressing the molecular and cellular aspects that link hNS to FENIB. We plan to shed light on how the hNS polymers are structured and grow, and how cells respond to the presence of such polymers. The presence of mutated hNS variants will be monitored in epileptic patients and the effects of any mutations found will be studied in cell and animal models (zebra fish) of disease, in order to establish the role of hNS in triggering FENIB symptoms. A number of synthetic molecules will be screened as potential inhibitors of hNS polymerisation in vitro, in cell lines and in the animal model. We plan to deliver basic information on the fundamentals of a poorly understood disease, information that may lead to the identification and the characterisation of potential drugs against FENIB.