Genes contributing to prion pathogenesis.
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.
Department of Neurology, University of California, San Francisco, CA, USA.|Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, USA.
Gültekin
G
Tamgüney
Department of Neurology, University of California, San Francisco, CA, USA.|Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, USA.
Kurt
K
Giles
Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA.
David V
DV
Glidden
Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, USA.
Pierre
P
Lessard
Department of Neurology, University of California, San Francisco, CA, USA.|Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, USA.
Holger
H
Wille
Department of Neurology, University of California, San Francisco, CA, USA.|Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, USA.
Patrick
P
Tremblay
Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, USA.
Darlene F
DF
Groth
Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, USA.
Fruma
F
Yehiely
Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, USA.
Carsten
C
Korth
Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, USA.
Richard C
RC
Moore
Department of Neurology, University of California, San Francisco, CA, USA.
Jörg
J
Tatzelt
INSERM, U602, and Université Paris 11, Villejuif, France.
Eric
E
Rubinstein
INSERM, U602, and Université Paris 11, Villejuif, France.
Claude
C
Boucheix
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
Xiaoping
X
Yang
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
Pamela
P
Stanley
Muscular and Neurodegenerative Disease Unit, University of Genova and G. Gaslini Pediatric Institute, Genova, Italy.
Michael P
MP
Lisanti
Department of Biochemistry and Oxford Glycobiology Institute, University of Oxford, Oxford, UK.
Raymond A
RA
Dwek
Department of Biochemistry and Oxford Glycobiology Institute, University of Oxford, Oxford, UK.
Pauline M
PM
Rudd
Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS, USA.
Jackob
J
Moskovitz
Institute for Human Genetics and Department of Pediatrics, University of California, San Francisco, CA, USA.
Charles J
CJ
Epstein
Department of Pathology and Laboratory Medicine, University of North Carolina Medical Center, Chapel Hill, NC, USA.
Tracey Dawson
TD
Cruz
Department of Pathology and Laboratory Medicine, University of North Carolina Medical Center, Chapel Hill, NC, USA.
William A
WA
Kuziel
Department of Pathology and Laboratory Medicine, University of North Carolina Medical Center, Chapel Hill, NC, USA.
Nobuyo
N
Maeda
Biotechnology Research and Innovation Center, Faculty of Health Sciences, University of Copenhagen, Denmark.
Jan
J
Sap
Departments of Neurology, Neuroscience and Graduate Program in Neuroscience, University of Minnesota, and Geriatric Research, Education and Clinical Center, Minneapolis Veterans Affairs Medical Center, Minneapolis, MN, USA.
Karen Hsiao
KH
Ashe
McLaughlin Research Institute, Great Falls, MT, USA.
George A
GA
Carlson
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Ina
I
Tesseur
Geriatric Research, Education and Clinical Center, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.|Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Tony
T
Wyss-Coray
Gladstone Institute of Neurological Disease, University of California, San Francisco, CA, USA.|Neuroscience Graduate Program, University of California, San Francisco, CA, USA.|Department of Neurology, University of California, San Francisco, CA, USA.
Lennart
L
Mucke
Cardiovascular Research Institute and Departments of Medicine and Pathology, University of California, San Francisco, CA, USA.|Gladstone Institute of Neurological Disease, University of California, San Francisco, CA, USA.
Karl H
KH
Weisgraber
Cardiovascular Research Institute and Departments of Medicine and Pathology, University of California, San Francisco, CA, USA.|Gladstone Institute of Neurological Disease, University of California, San Francisco, CA, USA.
Robert W
RW
Mahley
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA.|Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, USA.
Fred E
FE
Cohen
Department of Neurology, University of California, San Francisco, CA, USA.|Institute for Neurodegenerative Diseases, University of California, San Francisco, CA, USA.
Stanley B
SB
Prusiner
D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D018628:Gene Dosage; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017096:Prion Diseases / Q000235:genetics*; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D016019:Survival Analysis
D016564:Amyloid beta-Protein Precursor; D011328:Prions; D053573:Receptors, Interleukin-1 Type I; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1