Effect of the D178N mutation and the codon 129 polymorphism on the metabolism of the prion protein

Robert B. Petersen, Piero Parchi, Sandra L. Richardson, Cynthia B. Urig, Pierluigi Gambetti

Research output: Contribution to journalArticle

124 Citations (Scopus)

Abstract

Prion diseases are thought to be caused by the conversion of the normal, or cellular, prion protein (PrP(C)) into an abnormal protease-resistant conformation (PrP(res)). There are three familial forms of human prion disease, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome, and fatal familial insomnia (FFI) which are all expressed at advanced age despite the congenital presence of the mutant prion protein (PrP(M)). The cellular mechanisms that result in the age-dependent conversion of PrP(M) into PrP(res) and the unique phenotypes associated with each PrP(M) are unknown. FFI and a familial type of Creutzfeldt-Jakob disease (CJD178), share the D178N mutation in the PrP gene but have distinct phenotypes linked to codon 129, the site of a methionine/valine polymorphism (129M/V). We analyzed PrP processing in cells transfected with constructs reproducing the FFI and CJD178 genotypes. The D178N mutation results in instability of the mutant PrP which is partially corrected by N- glycosylation. Hence, only the glycosylated forms of PrP(M) reach the cell surface whereas the unglycosylated form is degraded. The unglycosylated PrP(M) is also under-represented in the brain of FFI patients validating the cell model. These results offer new insight into the effect of the D178N mutation on the metabolism of the priori protein.

Original languageEnglish
Pages (from-to)12661-12668
Number of pages8
JournalJournal of Biological Chemistry
Volume271
Issue number21
DOIs
Publication statusPublished - 1996

Fingerprint

Fatal Familial Insomnia
Polymorphism
Metabolism
Codon
PrPSc Proteins
Creutzfeldt-Jakob Syndrome
Mutation
Prion Diseases
Prions
Gerstmann-Straussler-Scheinker Disease
Glycosylation
Phenotype
Valine
Mutant Proteins
Protein C
Methionine
Conformations
Brain
Peptide Hydrolases
Genes

ASJC Scopus subject areas

  • Biochemistry

Cite this

Effect of the D178N mutation and the codon 129 polymorphism on the metabolism of the prion protein. / Petersen, Robert B.; Parchi, Piero; Richardson, Sandra L.; Urig, Cynthia B.; Gambetti, Pierluigi.

In: Journal of Biological Chemistry, Vol. 271, No. 21, 1996, p. 12661-12668.

Research output: Contribution to journalArticle

Petersen, Robert B. ; Parchi, Piero ; Richardson, Sandra L. ; Urig, Cynthia B. ; Gambetti, Pierluigi. / Effect of the D178N mutation and the codon 129 polymorphism on the metabolism of the prion protein. In: Journal of Biological Chemistry. 1996 ; Vol. 271, No. 21. pp. 12661-12668.
@article{1ec36c88458c4d6d9d84c6b06edce15d,
title = "Effect of the D178N mutation and the codon 129 polymorphism on the metabolism of the prion protein",
abstract = "Prion diseases are thought to be caused by the conversion of the normal, or cellular, prion protein (PrP(C)) into an abnormal protease-resistant conformation (PrP(res)). There are three familial forms of human prion disease, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome, and fatal familial insomnia (FFI) which are all expressed at advanced age despite the congenital presence of the mutant prion protein (PrP(M)). The cellular mechanisms that result in the age-dependent conversion of PrP(M) into PrP(res) and the unique phenotypes associated with each PrP(M) are unknown. FFI and a familial type of Creutzfeldt-Jakob disease (CJD178), share the D178N mutation in the PrP gene but have distinct phenotypes linked to codon 129, the site of a methionine/valine polymorphism (129M/V). We analyzed PrP processing in cells transfected with constructs reproducing the FFI and CJD178 genotypes. The D178N mutation results in instability of the mutant PrP which is partially corrected by N- glycosylation. Hence, only the glycosylated forms of PrP(M) reach the cell surface whereas the unglycosylated form is degraded. The unglycosylated PrP(M) is also under-represented in the brain of FFI patients validating the cell model. These results offer new insight into the effect of the D178N mutation on the metabolism of the priori protein.",
author = "Petersen, {Robert B.} and Piero Parchi and Richardson, {Sandra L.} and Urig, {Cynthia B.} and Pierluigi Gambetti",
year = "1996",
doi = "10.1074/jbc.271.21.12661",
language = "English",
volume = "271",
pages = "12661--12668",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "21",

}

TY - JOUR

T1 - Effect of the D178N mutation and the codon 129 polymorphism on the metabolism of the prion protein

AU - Petersen, Robert B.

AU - Parchi, Piero

AU - Richardson, Sandra L.

AU - Urig, Cynthia B.

AU - Gambetti, Pierluigi

PY - 1996

Y1 - 1996

N2 - Prion diseases are thought to be caused by the conversion of the normal, or cellular, prion protein (PrP(C)) into an abnormal protease-resistant conformation (PrP(res)). There are three familial forms of human prion disease, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome, and fatal familial insomnia (FFI) which are all expressed at advanced age despite the congenital presence of the mutant prion protein (PrP(M)). The cellular mechanisms that result in the age-dependent conversion of PrP(M) into PrP(res) and the unique phenotypes associated with each PrP(M) are unknown. FFI and a familial type of Creutzfeldt-Jakob disease (CJD178), share the D178N mutation in the PrP gene but have distinct phenotypes linked to codon 129, the site of a methionine/valine polymorphism (129M/V). We analyzed PrP processing in cells transfected with constructs reproducing the FFI and CJD178 genotypes. The D178N mutation results in instability of the mutant PrP which is partially corrected by N- glycosylation. Hence, only the glycosylated forms of PrP(M) reach the cell surface whereas the unglycosylated form is degraded. The unglycosylated PrP(M) is also under-represented in the brain of FFI patients validating the cell model. These results offer new insight into the effect of the D178N mutation on the metabolism of the priori protein.

AB - Prion diseases are thought to be caused by the conversion of the normal, or cellular, prion protein (PrP(C)) into an abnormal protease-resistant conformation (PrP(res)). There are three familial forms of human prion disease, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome, and fatal familial insomnia (FFI) which are all expressed at advanced age despite the congenital presence of the mutant prion protein (PrP(M)). The cellular mechanisms that result in the age-dependent conversion of PrP(M) into PrP(res) and the unique phenotypes associated with each PrP(M) are unknown. FFI and a familial type of Creutzfeldt-Jakob disease (CJD178), share the D178N mutation in the PrP gene but have distinct phenotypes linked to codon 129, the site of a methionine/valine polymorphism (129M/V). We analyzed PrP processing in cells transfected with constructs reproducing the FFI and CJD178 genotypes. The D178N mutation results in instability of the mutant PrP which is partially corrected by N- glycosylation. Hence, only the glycosylated forms of PrP(M) reach the cell surface whereas the unglycosylated form is degraded. The unglycosylated PrP(M) is also under-represented in the brain of FFI patients validating the cell model. These results offer new insight into the effect of the D178N mutation on the metabolism of the priori protein.

UR - http://www.scopus.com/inward/record.url?scp=17544366508&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=17544366508&partnerID=8YFLogxK

U2 - 10.1074/jbc.271.21.12661

DO - 10.1074/jbc.271.21.12661

M3 - Article

VL - 271

SP - 12661

EP - 12668

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 21

ER -