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

Citation
S. Capellari et al., Effect of the E200K mutation on prion protein metabolism - Comparative study of a cell model and human brain, AM J PATH, 157(2), 2000, pp. 613-622
Citations number
46
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Research/Laboratory Medicine & Medical Tecnology","Medical Research Diagnosis & Treatment
Journal title
AMERICAN JOURNAL OF PATHOLOGY
ISSN journal
0002-9440 → ACNP
Volume
157
Issue
2
Year of publication
2000
Pages
613 - 622
Database
ISI
SICI code
0002-9440(200008)157:2<613:EOTEMO>2.0.ZU;2-Y
Abstract
The hallmark of prion diseases is the cerebral accumulation of a conformati onally altered isoform (PrPSc) of a normal cellular protein, the prion prot ein (PrPC). In the inherited form, mutations in the prion protein gene are thought to cause the disease by altering the metabolism of the mutant PrP ( PrPM) engendering its conversion into PrPSc. We used a cell model to study biosynthesis and processing of PrPM carrying the glutamic acid to lysine su bstitution at residue 200 (E200K), which Is linked to the most common inher ited human prion disease. PrPM contained an aberrant glycan at residue 197 and generated an increased quantity of truncated fragments. In addition, Pr PM showed impaired transport of the unglycosylated isoform to the cell surf ace. Similar changes were found in the PrP isolated from brains of patients affected by the E200K variant of Creutzfeldt-Jakob disease. Although the c ellular PrPM displayed some characteristics of PrPSc, the PrPSc found in th e E200K brains was quantitatively and qualitatively different. We propose t hat the E200K mutation cause the same metabolic changes of PrPM in the cell model and in the brain. However, in the brain, PrPM undergoes additional m odifications, by an age-dependent mechanism that leads to the formation of PrPSc and the development of the disease.