Insoluble aggregates and protease-resistant conformers of prion protein in uninfected human brains.
Aggregated prion protein (PrPSc), which is detergent-insoluble and partially proteinase K (PK)-resistant, constitutes the major component of infectious prions that cause a group of transmissible spongiform encephalopathies in animals and humans. PrPSc derives from a detergent-soluble and PK-sensitive cellular prion protein (PrPC) through an alpha-helix to beta-sheet transition. This transition confers on the PrPSc molecule unique physicochemical and biological properties, including insolubility in nondenaturing detergents, an enhanced tendency to form aggregates, resistance to PK digestion, and infectivity, which together are regarded as the basis for distinguishing PrPSc from PrPC. Here we demonstrate, using sedimentation and size exclusion chromatography, that small amounts of detergent-insoluble PrP aggregates are present in uninfected human brains. Moreover, PK-resistant PrP core fragments are detectable following PK treatment. This is the first study that provides experimental evidence supporting the hypothesis that there might be silent prions lying dormant in normal human brains.
Yuan
Jue
J
Department of Pathology and National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Xiao
Xiangzhu
X
McGeehan
John
J
Dong
Zhiqian
Z
Cali
Ignazio
I
Fujioka
Hisashi
H
Kong
Qingzhong
Q
Kneale
Geoff
G
Gambetti
Pierluigi
P
Zou
Wen-Quan
WQ
D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002417:Cattle; D006224:Cricetinae; D006801:Humans; D010447:Peptide Hydrolases / Q000378:metabolism*; D011328:Prions / Q000737:chemistry* / Q000378:metabolism*; D012995:Solubility
D011328:Prions; D010447:Peptide Hydrolases