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From: TSS ()
The most infectious prion protein particles Jay R. Silveira1, Gregory J. Raymond1, Andrew G. Hughson1, Richard E. Race1, Valerie L. Sim1, Stanley F. Hayes2 and Byron Caughey1 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 disease1, 2. Abnormal deposits in TSEs are rich in PrPres, a protease-resistant form of the PrP protein with the ability to convert the normal, protease-sensitive form of the protein (PrPsen) into PrPres (ref. 3). TSEs can be transmitted between organisms by an enigmatic agent (prion) that contains PrPres (refs 4 and 5). To evaluate systematically the relationship between infectivity, converting activity and the size of various PrPres-containing aggregates, PrPres 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 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. Top of page Received 15 May 2005; Accepted 24 June 2005 http://www.nature.com/nature/journal/v437/n7056/abs/nature03989.html Editor's Summary Prions: form and infectivity -------------------------------------------------------------------------------- The prospects of limiting the spread of transmissible spongiform encephalopathies such as Creutzfeldt−Jakob disease depend in part on identifying the most infectious forms of the prions that carry the diseases. A study of modified scrapie prions shows that clusters of 14 to 28 prion proteins are the most infectious and that clusters of less than six molecules have virtually no infectivity. That could have implications for the treatment of diseases such as Alzheimer's and Parkinson's, characterized by deposition of prion-related amyloid fibrils. It's possible that efforts to alleviate symptoms by destabilizing these large protein aggregates might make things worse by producing smaller, more infective particles. Two other papers in this issue tackle fundamental aspects of the biology of prions and amyloid fibrils. The conversion of the yeast protein Sup35 to its prion form does not need to happen during the synthesis of Sup35 — mature and fully functional molecules can readily join a prion seed. This remodelling of the mature protein is accompanied by the immediate loss of its activity. And a study of a 'designed' amyloid fibril made from ribonuclease A reveals that amyloid containing native-like molecules can retain enzyme activity. This involves a domain swap with the neighbouring protein, and supports the 'zipper-spine model' for -amyloid structures. News and Views: Structural biology: Fibres hinge on swapped domains Andrew D. Miranker doi: 10.1038/437197a Full Text | PDF (309K) Letter: The most infectious prion protein particles doi: 10.1038/nature03989 First paragraph | Full Text | PDF (442K) | Supplementary information Letter: Prion protein remodelling confers an immediate phenotypic switch doi: 10.1038/nature03981 First paragraph | Full Text | PDF (343K) | Supplementary information Letter: Amyloid-like fibrils of ribonuclease A with three-dimensional domain-swapped and native-like structure doi: 10.1038/nature03916 TSS
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