Genetic, cellular, and structural basis of the neurodegenerative pathology FENIB

Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a rare neurodegenerative disorder of genetic origin caused by mutations in neuroserpin that lead to the formation of linked neuroserpin chains (polymers) within neurons. Neuroserpin polymers induce neuronal toxicity and death through mechanisms incompletely understood, and the linking mechanism of polymer formation is still unknown. We propose three approaches to address these issues. The first one is based on characterising novel mutations in neuroserpin in a cellular model, so we can find out if all the mutations that cause FENIB induce polymer formation and also confirm the diagnosis of new cases of FENIB. The second one is based on creating a human neuronal model of FENIB by directing the production of wild type and polymerogenic forms of neuroserpin in cells that can be transformed into neurons in laboratory cultures; this system will be used to study the neuronal mechanisms of toxicity. Our studies using mouse neurons support the involvement of oxidative stress and mitochondrial alterations, but studies in human neurons are needed to confirm these findings in FENIB, and to discover other neuronal alterations that cause the disease. The third approach aims to define the polymerisation mechanism of neuroserpin through detailed molecular studies in collaboration with Prof. Lomas and Dr. Irving at University College London (UK); we expect to understand the difference in the propensity to polymer formation for different variants of NS and its correlation with the associated clinical phenotypes.