title: Prion clearance in bigenic mice.
abstract: The clearance of prions from the brain was investigated in bigenic mice designated Tg(tTA : PrP(+/0))3, in which expression of the cellular prion protein (PrP(C)) was regulated by oral doxycycline administration. With suppression of PrP(C) expression, the incubation time for RML prions was prolonged almost threefold from approximately 150 to approximately 430 days. To determine the clearance rate of disease-causing PrP(Sc), bigenic mice were given oral doxycycline beginning 98 days after inoculation with RML prions and sacrificed at various time points over the subsequent 56 days. The half-life (t1/2) for PrP(Sc) was approximately 1.5 days in mouse brain, in reasonable agreement with the apparent t1/2 of 30 h that was determined in a separate study for scrapie-infected mouse neuroblastoma (ScN2a) cells in culture. Both protease-sensitive and -resistant conformers of PrP(Sc) were cleared at the same rate. The t1/2 value for PrP(C) clearance from brain was approximately 18 h, which was considerably longer than the t1/2 of 5 h found in ScN2a cells. The capability of the brain to clear prions raises the possibility that PrP(Sc) is normally made at low levels and continually cleared, and that PrP(Sc) may have a function in cellular metabolism. Moreover, these bigenic mice make it possible to determine both components of PrP(Sc) accumulation, i.e. the rates of formation and clearance, for various strains of prions exhibiting different incubation times.
authors.affiliation: Department of Neurology, University of California, 513 Parnassus Ave, San Francisco, CA 94143, USA.|Institute for Neurodegenerative Diseases, University of California, 513 Parnassus Ave, San Francisco, CA 94143, USA.
authors.forename: Jiri G
authors.initials: JG
authors.lastname: Safar
authors.affiliation: Department of Pathology, University of California, 513 Parnassus Ave, San Francisco, CA 94143, USA.|Institute for Neurodegenerative Diseases, University of California, 513 Parnassus Ave, San Francisco, CA 94143, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: DeArmond
authors.affiliation: Institute for Neurodegenerative Diseases, University of California, 513 Parnassus Ave, San Francisco, CA 94143, USA.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kociuba
authors.affiliation: Institute for Neurodegenerative Diseases, University of California, 513 Parnassus Ave, San Francisco, CA 94143, USA.
authors.forename: Camille
authors.initials: C
authors.lastname: Deering
authors.affiliation: Institute for Neurodegenerative Diseases, University of California, 513 Parnassus Ave, San Francisco, CA 94143, USA.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Didorenko
authors.affiliation: Department of Pathology, University of California, 513 Parnassus Ave, San Francisco, CA 94143, USA.
authors.forename: Essia
authors.initials: E
authors.lastname: Bouzamondo-Bernstein
authors.affiliation: Department of Biochemistry and Biophysics, University of California, 513 Parnassus Ave, San Francisco, CA 94143, USA.|Department of Neurology, University of California, 513 Parnassus Ave, San Francisco, CA 94143, USA.|Institute for Neurodegenerative Diseases, University of California, 513 Parnassus Ave, San Francisco, CA 94143, USA.
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Prusiner
authors.affiliation: Department of Neurology, University of California, 513 Parnassus Ave, San Francisco, CA 94143, USA.|Institute for Neurodegenerative Diseases, University of California, 513 Parnassus Ave, San Francisco, CA 94143, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Tremblay
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D004318:Doxycycline / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D018620:PrPSc Proteins / Q000378:metabolism; D011328:Prions / Q000378:metabolism*; D011489:Protein Denaturation; D012608:Scrapie / Q000378:metabolism*
chemical_list: D018620:PrPSc Proteins; D011328:Prions; D004318:Doxycycline