Effect of the E200K mutation on prion protein metabolism: Comparative study of a cell model and human brain

S. Capellari, P. Parchi, C. M. Russo, J. Sanford, M. S. Sy, P. Gambetti, R. B. Petersen

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

The hallmark of priori diseases is the cerebral accumulation of a conformationally altered isoform (PrP(Sc)) of a normal cellular protein, the prion protein (PrP(C)). In the inherited form, mutations in the priori protein gene are thought to cause the disease by altering the metabolism of the mutant PrP (PrP(M)) engendering its conversion into PrP(Sc). We used a cell model to study biosynthesis and processing of PrP(M) carrying the glutamic acid to lysine substitution at residue 200 (E200K), which is linked to the most common inherited human prion disease. PrP(M) contained an aberrant glycan at residue 197 and generated an increased quantity of truncated fragments. In addition, PrP(M) showed impaired transport of the un-glycosylated isoform to the cell surface. Similar changes were found in the PrP isolated from brains of patients affected by the E200K variant of Creutzfeldt-Jakob disease. Although the cellular PrP(M) displayed some characteristics of PrP(Sc), the PrP(Sc) found in the E200K brains was quantitatively and qualitatively different. We propose that the E200K mutation cause the same metabolic changes of PrP(M) in the cell model and in the brain. However, in the brain, PrP(M) undergoes additional modifications, by an age-dependent mechanism that leads to the formation of PrP(Sc) and the development of the disease.

Original languageEnglish
Pages (from-to)613-622
Number of pages10
JournalAmerican Journal of Pathology
Volume157
Issue number2
Publication statusPublished - 2000

Fingerprint

Mutation
Brain
Protein Isoforms
Creutzfeldt-Jakob Syndrome
Prion Diseases
Protein C
Lysine
Polysaccharides
Glutamic Acid
Proteins
Prion Proteins

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Effect of the E200K mutation on prion protein metabolism : Comparative study of a cell model and human brain. / Capellari, S.; Parchi, P.; Russo, C. M.; Sanford, J.; Sy, M. S.; Gambetti, P.; Petersen, R. B.

In: American Journal of Pathology, Vol. 157, No. 2, 2000, p. 613-622.

Research output: Contribution to journalArticle

Capellari, S. ; Parchi, P. ; Russo, C. M. ; Sanford, J. ; Sy, M. S. ; Gambetti, P. ; Petersen, R. B. / Effect of the E200K mutation on prion protein metabolism : Comparative study of a cell model and human brain. In: American Journal of Pathology. 2000 ; Vol. 157, No. 2. pp. 613-622.
@article{557f65ce29f043e7a822c604341a6371,
title = "Effect of the E200K mutation on prion protein metabolism: Comparative study of a cell model and human brain",
abstract = "The hallmark of priori diseases is the cerebral accumulation of a conformationally altered isoform (PrP(Sc)) of a normal cellular protein, the prion protein (PrP(C)). In the inherited form, mutations in the priori protein gene are thought to cause the disease by altering the metabolism of the mutant PrP (PrP(M)) engendering its conversion into PrP(Sc). We used a cell model to study biosynthesis and processing of PrP(M) carrying the glutamic acid to lysine substitution at residue 200 (E200K), which is linked to the most common inherited human prion disease. PrP(M) contained an aberrant glycan at residue 197 and generated an increased quantity of truncated fragments. In addition, PrP(M) showed impaired transport of the un-glycosylated isoform to the cell surface. Similar changes were found in the PrP isolated from brains of patients affected by the E200K variant of Creutzfeldt-Jakob disease. Although the cellular PrP(M) displayed some characteristics of PrP(Sc), the PrP(Sc) found in the E200K brains was quantitatively and qualitatively different. We propose that the E200K mutation cause the same metabolic changes of PrP(M) in the cell model and in the brain. However, in the brain, PrP(M) undergoes additional modifications, by an age-dependent mechanism that leads to the formation of PrP(Sc) and the development of the disease.",
author = "S. Capellari and P. Parchi and Russo, {C. M.} and J. Sanford and Sy, {M. S.} and P. Gambetti and Petersen, {R. B.}",
year = "2000",
language = "English",
volume = "157",
pages = "613--622",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "2",

}

TY - JOUR

T1 - Effect of the E200K mutation on prion protein metabolism

T2 - Comparative study of a cell model and human brain

AU - Capellari, S.

AU - Parchi, P.

AU - Russo, C. M.

AU - Sanford, J.

AU - Sy, M. S.

AU - Gambetti, P.

AU - Petersen, R. B.

PY - 2000

Y1 - 2000

N2 - The hallmark of priori diseases is the cerebral accumulation of a conformationally altered isoform (PrP(Sc)) of a normal cellular protein, the prion protein (PrP(C)). In the inherited form, mutations in the priori protein gene are thought to cause the disease by altering the metabolism of the mutant PrP (PrP(M)) engendering its conversion into PrP(Sc). We used a cell model to study biosynthesis and processing of PrP(M) carrying the glutamic acid to lysine substitution at residue 200 (E200K), which is linked to the most common inherited human prion disease. PrP(M) contained an aberrant glycan at residue 197 and generated an increased quantity of truncated fragments. In addition, PrP(M) showed impaired transport of the un-glycosylated isoform to the cell surface. Similar changes were found in the PrP isolated from brains of patients affected by the E200K variant of Creutzfeldt-Jakob disease. Although the cellular PrP(M) displayed some characteristics of PrP(Sc), the PrP(Sc) found in the E200K brains was quantitatively and qualitatively different. We propose that the E200K mutation cause the same metabolic changes of PrP(M) in the cell model and in the brain. However, in the brain, PrP(M) undergoes additional modifications, by an age-dependent mechanism that leads to the formation of PrP(Sc) and the development of the disease.

AB - The hallmark of priori diseases is the cerebral accumulation of a conformationally altered isoform (PrP(Sc)) of a normal cellular protein, the prion protein (PrP(C)). In the inherited form, mutations in the priori protein gene are thought to cause the disease by altering the metabolism of the mutant PrP (PrP(M)) engendering its conversion into PrP(Sc). We used a cell model to study biosynthesis and processing of PrP(M) carrying the glutamic acid to lysine substitution at residue 200 (E200K), which is linked to the most common inherited human prion disease. PrP(M) contained an aberrant glycan at residue 197 and generated an increased quantity of truncated fragments. In addition, PrP(M) showed impaired transport of the un-glycosylated isoform to the cell surface. Similar changes were found in the PrP isolated from brains of patients affected by the E200K variant of Creutzfeldt-Jakob disease. Although the cellular PrP(M) displayed some characteristics of PrP(Sc), the PrP(Sc) found in the E200K brains was quantitatively and qualitatively different. We propose that the E200K mutation cause the same metabolic changes of PrP(M) in the cell model and in the brain. However, in the brain, PrP(M) undergoes additional modifications, by an age-dependent mechanism that leads to the formation of PrP(Sc) and the development of the disease.

UR - http://www.scopus.com/inward/record.url?scp=0033873642&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033873642&partnerID=8YFLogxK

M3 - Article

C2 - 10934164

AN - SCOPUS:0033873642

VL - 157

SP - 613

EP - 622

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 2

ER -