The hydrophobic core region governs mutant prion protein aggregation and intracellular retention.

The Biochemical Journal
Emiliano BiasiniR Chiesa

Abstract

Approx. 15% of human prion diseases have a pattern of autosomal dominant inheritance, and are linked to mutations in the gene encoding PrP (prion protein), a GPI (glycosylphosphatidylinositol)-anchored protein whose function is not clear. The cellular mechanisms by which PrP mutations cause disease are also not known. Soon after synthesis in the ER (endoplasmic reticulum), several mutant PrPs misfold and become resistant to phospholipase cleavage of their GPI anchor. The biosynthetic maturation of the misfolded molecules in the ER is delayed and, during transit in the secretory pathway, they form detergent-insoluble and protease-resistant aggregates, suggesting that intracellular PrP aggregation may play a pathogenic role. We have investigated the consequence of deleting residues 114-121 within the hydrophobic core of PrP on the aggregation and cellular localization of two pathogenic mutants that accumulate in the ER and Golgi apparatus. Compared with their full-length counterparts, the deleted molecules formed smaller protease-sensitive aggregates and were more efficiently transported to the cell surface and released by phospholipase cleavage. These results indicate that mutant PrP aggregation and intracellular retention are c...Continue Reading

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Citations

Mar 10, 2011·The Journal of Biological Chemistry·Isaac H SolomonDavid A Harris
Dec 27, 2013·International Journal of Cell Biology·Assunta SenatoreRoberto Chiesa
Feb 13, 2015·Proceedings of the National Academy of Sciences of the United States of America·Jinko SawashitaKeiichi Higuchi
Apr 15, 2020·Nature Structural & Molecular Biology·Calina GlynnJose A Rodriguez
Mar 5, 2021·The Journal of Biological Chemistry·Elena RestelliRoberto Chiesa

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