title: Uptake and degradation of protease-sensitive and -resistant forms of abnormal human prion protein aggregates by human astrocytes.
abstract: Sporadic Creutzfeldt-Jakob disease is the most common of the human prion diseases, a group of rare, transmissible, and fatal neurologic diseases associated with the accumulation of an abnormal form (PrP(Sc)) of the host prion protein. In sporadic Creutzfeldt-Jakob disease, disease-associated PrP(Sc) is present not only as an aggregated, protease-resistant form but also as an aggregated protease-sensitive form (sPrP(Sc)). Although evidence suggests that sPrP(Sc) may play a role in prion pathogenesis, little is known about how it interacts with cells during prion infection. Here, we show that protease-sensitive abnormal PrP aggregates derived from patients with sporadic Creutzfeldt-Jakob disease are taken up and degraded by immortalized human astrocytes similarly to abnormal PrP aggregates that are resistant to proteases. Our data suggest that relative proteinase K resistance does not significantly influence the astrocyte's ability to degrade PrP(Sc). Furthermore, the cell does not appear to distinguish between sPrP(Sc) and protease-resistant PrP(Sc), suggesting that sPrP(Sc) could contribute to prion infection.
authors.affiliation: Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana.
authors.forename: Young Pyo
authors.initials: YP
authors.lastname: Choi
authors.affiliation: National Creutzfeldt Jakob Disease Research & Surveillance Unit, School of Clinical Sciences, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Head
authors.affiliation: National Creutzfeldt Jakob Disease Research & Surveillance Unit, School of Clinical Sciences, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: James W
authors.initials: JW
authors.lastname: Ironside
authors.affiliation: Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana. Electronic address: spriola@niaid.nih.gov.
authors.forename: Suzette A
authors.initials: SA
authors.lastname: Priola
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D007562:Creutzfeldt-Jakob Syndrome / Q000378:metabolism*; D019286:Endopeptidase K / Q000737:chemistry; D000939:Epitopes / Q000737:chemistry; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008856:Microscopy, Fluorescence; D010447:Peptide Hydrolases / Q000737:chemistry*; D010772:Phosphotungstic Acid / Q000737:chemistry; D018621:PrPC Proteins / Q000378:metabolism*; D018620:PrPSc Proteins / Q000378:metabolism; D017096:Prion Diseases / Q000378:metabolism; D011328:Prions / Q000378:metabolism*
chemical_list: D000939:Epitopes; D018621:PrPC Proteins; D018620:PrPSc Proteins; D011328:Prions; D010772:Phosphotungstic Acid; D010447:Peptide Hydrolases; D019286:Endopeptidase K