Genes contributing to prion pathogenesis.

TY - JOUR

T1 - Genes contributing to prion pathogenesis.

AU - Tamgüney, Gültekin

AU - Giles, Kurt

AU - Glidden, David V

AU - Lessard, Pierre

AU - Wille, Holger

AU - Tremblay, Patrick

AU - Groth, Darlene F

AU - Yehiely, Fruma

AU - Korth, Carsten

AU - Moore, Richard C

AU - Tatzelt, Jörg

AU - Rubinstein, Eric

AU - Boucheix, Claude

AU - Yang, Xiaoping

AU - Stanley, Pamela

AU - Lisanti, Michael P

AU - Dwek, Raymond A

AU - Rudd, Pauline M

AU - Moskovitz, Jackob

AU - Epstein, Charles J

AU - Cruz, Tracey Dawson

AU - Kuziel, William A

AU - Maeda, Nobuyo

AU - Sap, Jan

AU - Ashe, Karen Hsiao

AU - Carlson, George A

AU - Tesseur, Ina

AU - Wyss-Coray, Tony

AU - Mucke, Lennart

AU - Weisgraber, Karl H

AU - Mahley, Robert W

AU - Cohen, Fred E

AU - Prusiner, Stanley B

PY - 2008

Y1 - 2008

N2 - Prion diseases are caused by conversion of a normally folded, non-pathogenic isoform of the prion protein (PrP(C)) to a misfolded, pathogenic isoform (PrP(Sc)). Prion inoculation experiments in mice expressing homologous PrP(C) molecules on different genetic backgrounds displayed different incubation times, indicating that the conversion reaction may be influenced by other gene products. To identify genes that contribute to prion pathogenesis, we analysed incubation times of prions in mice in which the gene product was inactivated, knocked out or overexpressed. We tested 20 candidate genes, because their products either colocalize with PrP, are associated with Alzheimer's disease, are elevated during prion disease, or function in PrP-mediated signalling, PrP glycosylation, or protein maintenance. Whereas some of the candidates tested may have a role in the normal function of PrP(C), our data show that many genes previously implicated in prion replication have no discernible effect on the pathogenesis of prion disease. While most genes tested did not significantly affect survival times, ablation of the amyloid beta (A4) precursor protein (App) or interleukin-1 receptor, type I (Il1r1), and transgenic overexpression of human superoxide dismutase 1 (SOD1) prolonged incubation times by 13, 16 and 19 %, respectively.

AB - Prion diseases are caused by conversion of a normally folded, non-pathogenic isoform of the prion protein (PrP(C)) to a misfolded, pathogenic isoform (PrP(Sc)). Prion inoculation experiments in mice expressing homologous PrP(C) molecules on different genetic backgrounds displayed different incubation times, indicating that the conversion reaction may be influenced by other gene products. To identify genes that contribute to prion pathogenesis, we analysed incubation times of prions in mice in which the gene product was inactivated, knocked out or overexpressed. We tested 20 candidate genes, because their products either colocalize with PrP, are associated with Alzheimer's disease, are elevated during prion disease, or function in PrP-mediated signalling, PrP glycosylation, or protein maintenance. Whereas some of the candidates tested may have a role in the normal function of PrP(C), our data show that many genes previously implicated in prion replication have no discernible effect on the pathogenesis of prion disease. While most genes tested did not significantly affect survival times, ablation of the amyloid beta (A4) precursor protein (App) or interleukin-1 receptor, type I (Il1r1), and transgenic overexpression of human superoxide dismutase 1 (SOD1) prolonged incubation times by 13, 16 and 19 %, respectively.

U2 - 10.1099/vir.0.2008/001255-0

DO - 10.1099/vir.0.2008/001255-0

M3 - Journal article

C2 - 18559949

SN - 0022-1317

VL - 89

SP - 1777

EP - 1788

JO - Journal of General Virology

JF - Journal of General Virology

IS - Pt 7

ER -