Prion protein aggregation reverted by low temperature in transfected cells carrying a prion protein gene mutation.
Prion diseases are characterized by the conversion of the normal cellular prion protein (PrPC), a glycoprotein that is anchored to the cell membrane by a glycosylphosphatidylinositol moiety, into an isoform that is protease-resistant (PrPres) and pathogenic. In inherited prion diseases, mutations in the prion protein (PrPM) engender the conversion of PrPM into PrPres. We developed a cell model of Gerstmann-Sträussler-Scheinker disease, a neurodegenerative condition characterized by PrPM-containing amyloid deposits and neuronal loss, by expressing the Gerstmann-Sträussler-Scheinker haplotype Q217R-129V in human neuroblastoma cells. By comparison to PrPC, this genotype results in the following alterations of PrPM: 1) expression of an aberrant form lacking the glycosylphosphatidylinositol anchor, 2) increased aggregation and protease resistance, and 3) impaired transport to the cell surface. Most of these alterations are temperature-sensitive, indicating that they are due to misfolding of PrPM.
Singh
N
N
Division of Neuropathology, Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Zanusso
G
G
Chen
S G
SG
Fujioka
H
H
Richardson
S
S
Gambetti
P
P
Petersen
R B
RB
D002462:Cell Membrane / Q000378:metabolism; D003080:Cold Temperature; D005838:Genotype; D016098:Gerstmann-Straussler-Scheinker Disease / Q000235:genetics; D006801:Humans; D009154:Mutation; D011328:Prions / Q000737:chemistry / Q000235:genetics*; D017510:Protein Folding; D013499:Surface Properties; D014162:Transfection; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000378:metabolism
D011328:Prions; D010738:Type C Phospholipases