title: Initial fate of prions upon peripheral infection: half-life, distribution, clearance, and tissue uptake.
abstract: Prion diseases are infectious neurodegenerative disorders associated with the misfolded prion protein (PrP(Sc)), which appears to be the sole component of the infectious agent (termed prion). To produce disease, prions have to be absorbed into the body and reach sufficient quantities in the brain. Very little is known about the biological mechanisms controlling the initial fate of prions. Here, we studied the systemic pharmacokinetics and biodistribution of PrP(Sc) in vivo. After an intravenous injection of highly purified radiolabeled or native unlabeled PrP(Sc), the protein was eliminated rapidly from the serum (half-life of 3.24 h), mostly through tissue uptake. The quantity of intact PrP(Sc) reaching the brain was ∼ 0.2% of the injected dose per gram of brain tissue (ID/g). The highest levels were found in liver (∼ 20% ID/g), spleen (∼ 13% ID/g), and kidney (∼ 7.4% ID/g). Cell surface PrP(C) does not appear to play a role in PrP(Sc) pharmacokinetics, since the infectious protein distributed similarly in wild-type and PrP-null mice. To measure tissue uptake kinetics and biodistribution accurately, vascular space in tissues was measured with radioactively labeled albumin coinjected with radioactively labeled PrP(Sc). Our results provide a fundamental pharmacokinetic characterization of PrP(Sc) in vivo, which may be relevant to estimate tissue risks and mechanisms of prion neuroinvasion and to identify novel therapeutic strategies.
authors.affiliation: Department of Neurology, The University of Texas Medical School at Houston, Houston, Texas 77030, USA. akihiko.urayama@uth.tmc.edu
authors.forename: Akihiko
authors.initials: A
authors.lastname: Urayama
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Morales
authors.forename: Michael L
authors.initials: ML
authors.lastname: Niehoff
authors.forename: William A
authors.initials: WA
authors.lastname: Banks
authors.forename: Claudio
authors.initials: C
authors.lastname: Soto
mesh_terms: D000818:Animals; D001693:Biological Transport, Active; D001921:Brain / Q000378:metabolism; D006207:Half-Life; D007275:Injections, Intravenous; D008657:Metabolic Clearance Rate; D051379:Mice; D018620:PrPSc Proteins / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D017096:Prion Diseases / Q000097:blood / Q000378:metabolism*; D055550:Protein Stability; D012608:Scrapie / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D018620:PrPSc Proteins