Proteasomal degradation and N-terminal protease resistance of the codon 145 mutant prion protein

Citation
G. Zanusso et al., Proteasomal degradation and N-terminal protease resistance of the codon 145 mutant prion protein, J BIOL CHEM, 274(33), 1999, pp. 23396-23404
Citations number
47
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
0021-9258 → ACNP
Volume
274
Issue
33
Year of publication
1999
Pages
23396 - 23404
Database
ISI
SICI code
0021-9258(19990813)274:33<23396:PDANPR>2.0.ZU;2-J
Abstract
An amber mutation at codon 145 (Y145stop) of the prion protein gene results in a variant of an inherited human prion disease named Gerstmann-Straussle r-Scheinker syndrome. The characteristic features of this disorder include amyloid deposits of prion protein in cerebral parenchyma and vessels. We ha ve studied the biosynthesis and processing of the prion protein containing the Y145stop mutation (PrP145) in, transfected human neuroblastoma cells in an attempt to clarify the effect of the mutation on the metabolism of PrP1 45 and to gain insight into the underlying pathogenetic mechanism. Our resu lts demonstrate that 1) a significant proportion of PrP145 is not processed post-translationally and retains the N-terminal signal peptide, 2) most Pr P145 is degraded very rapidly by the proteasome-mediated pathway, 3) blocka ge of proteasomal degradation results in intracellular accumulation of PrP1 45, 4) most of the accumulated PrP145 is detergent-insoluble, and both the detergent-soluble and -insoluble fractions are resistant to mild proteinase K (PK) treatment, suggesting that PK resistance is not simply because of a ggregation. The present study demonstrates for the first time that a mutant prion protein is degraded through the proteasomal pathway and acquires PK- resistance if degradation is impaired.