The most infectious prion protein particles.
Neurodegenerative diseases such as Alzheimer's, Parkinson's and the transmissible spongiform encephalopathies (TSEs) are characterized by abnormal protein deposits, often with large amyloid fibrils. However, questions have arisen as to whether such fibrils or smaller subfibrillar oligomers are the prime causes of disease. Abnormal deposits in TSEs are rich in PrP(res), a protease-resistant form of the PrP protein with the ability to convert the normal, protease-sensitive form of the protein (PrP(sen)) into PrP(res) (ref. 3). TSEs can be transmitted between organisms by an enigmatic agent (prion) that contains PrP(res) (refs 4 and 5). To evaluate systematically the relationship between infectivity, converting activity and the size of various PrP(res)-containing aggregates, PrP(res) was partially disaggregated, fractionated by size and analysed by light scattering and non-denaturing gel electrophoresis. Our analyses revealed that with respect to PrP content, infectivity and converting activity peaked markedly in 17-27-nm (300-600 kDa) particles, whereas these activities were substantially lower in large fibrils and virtually absent in oligomers of < or =5 PrP molecules. These results suggest that non-fibrillar particles, with masses equivalent to 14-28 PrP molecules, are the most efficient initiators of TSE disease.
Silveira
Jay R
JR
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana 59840, USA.
Raymond
Gregory J
GJ
Hughson
Andrew G
AG
Race
Richard E
RE
Sim
Valerie L
VL
Hayes
Stanley F
SF
Caughey
Byron
B
D000818:Animals; D001921:Brain; D005591:Chemical Fractionation; D006224:Cricetinae; D004591:Electrophoresis, Polyacrylamide Gel; D015151:Immunoblotting; D046529:Microscopy, Electron, Transmission; D008970:Molecular Weight; D018620:PrPSc Proteins / Q000737:chemistry* / Q000302:isolation & purification / Q000472:pathogenicity* / Q000648:ultrastructure; D017096:Prion Diseases / Q000378:metabolism* / Q000635:transmission*; D020836:Protein Structure, Quaternary; D012542:Scattering, Radiation
D018620:PrPSc Proteins