期刊
FASEB JOURNAL
卷 25, 期 8, 页码 2792-2803出版社
WILEY
DOI: 10.1096/fj.11-180729
关键词
PrPSc; pharmacokinetics; blood-brain barrier
资金
- U.S. National Institutes of Health [R01 NS050547, P01 AI77774]
Prion diseases are infectious neurodegenerative disorders associated with the misfolded prion protein (PrPSc), 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 PrPSc in vivo. After an intravenous injection of highly purified radiolabeled or native unlabeled PrPSc, the protein was eliminated rapidly from the serum (half-life of 3.24 h), mostly through tissue uptake. The quantity of intact PrPSc 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 PrPC does not appear to play a role in PrPSc 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 PrPSc. Our results provide a fundamental pharmacokinetic characterization of PrPSc 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
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