Structure analysis of human Prion protein involved in Sporadic Fatal Insomnia

Abstract

Prion disorders are the root cause of Transmissible Spongiform Encephalopathies (TSE), a group of lethal diseases portrayed by progressive neurodegeneration and spongiosis. In recent years, researchers have come to understand that it is not the endogenous presence of Prions itself that causes neurodegeneration, but the amount of prion proteins that accumulates in the nervous tissue, leading them to exert neurotoxicity. More specifically, the cause of these disorders is mapped to several mutations that can bring the prion protein structure to a disordered permanent misfolded state. Our research is focused on Sporadic Fatal Insomnia (sFI), a rare TSE characterized by severe and chronic insomnia, leading to a life expectancy estimation of about two and a half years, from the onset of the first symptoms. The goal of this work was to analyze through computational studies the structure of the native human Prion Protein (PrPnat) and compare it with the toxic form (FI-Prion) which causes disease. Our findings show that the structure of the human mutant FI-Prion, responsible for Sporadic Fatal Insomnia is more flexible than the native human form PrPnat. Specific regions of the mutant seem to fluctuate more freely than the corresponding loops in the native form. We also identified amino acids Tyr128 and Met129 to be the key residues playing a major role in the manifestation of the disease. Therefore, weve learnt that the FI-Prion is more flexible than PrPnat. In addition, we also confirmed that sporadic fatal insomnia is undoubtedly an infectious disease.