Initial fate of prions upon peripheral infection: half-life, distribution, clearance, and tissue uptake

Soto, Claudio; Niehoff, Michael L.; Urayama, Akihiko; Banks, William A.; Morales, Rodrigo

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 similar to 0.2% of the injected dose per gram of brain tissue (ID/g). The highest levels were found in liver (similar to 20% ID/g), spleen (similar to 13% ID/g), and kidney (similar to 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.-Urayama, A., Morales, R., Niehoff, M. L., Banks, W. A., Soto, C. Initial fate of prions upon peripheral infection: half-life, distribution, clearance, and tissue uptake FASEB J. 25, 2792-2803 (2011). www.fasebj.org

Más información

Título según WOS: ID WOS:000293337800027 Not found in local WOS DB
Título de la Revista: FASEB JOURNAL
Volumen: 25
Número: 8
Editorial: Wiley
Fecha de publicación: 2011
Página de inicio: 2792
Página final: 2803
DOI:

10.1096/fj.11-180729

Notas: ISI