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 closely related and depend critically on the integrity of the hydrophobic core. The discovery that Δ114–121 counteracts misfolding and improves the cellular trafficking of mutant PrP provides an unprecedented model for assessing the role of intracellular aggregation in the pathogenesis of prion diseases.
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The hydrophobic core region governs mutant prion protein aggregation and intracellular retention
Emiliano Biasini*† 1 2 , Laura Tapella*†, Elena Restelli*†, Manuela Pozzoli*†, Tania Massignan*‡ and Roberto Chiesa*† 2
Follow Biochemical Journal
, Volume 430 (3)
Portland Press – Sep 15, 2010
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