In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 103, No. 50 ( 2006-12-12), p. 19105-19110
Abstract:
On passaging synthetic prions, two isolates emerged with incubation times differing by nearly 100 days. Using conformational-stability assays, we determined the guanidine hydrochloride (Gdn·HCl) concentration required to denature 50% of disease-causing prion protein (PrP Sc ) molecules, denoted as the [Gdn·HCl] 1/2 value. For the two prion isolates enciphering shorter and longer incubation times, [Gdn·HCl] 1/2 values of 2.9 and 3.7 M, respectively, were found. Intrigued by this result, we measured the conformational stabilities of 30 prion isolates from synthetic and naturally occurring sources that had been passaged in mice. When the incubation times were plotted as a function of the [Gdn·HCl] 1/2 values, a linear relationship was found with a correlation coefficient of 0.93. These findings demonstrate that ( i ) less stable prions replicate more rapidly than do stable prions, and ( ii ) a continuum of PrP Sc structural states enciphers a multitude of incubation-time phenotypes. Our data argue that cellular machinery must exist for propagating a large number of different PrP Sc conformers, each of which enciphers a distinct biological phenotype as reflected by a specific incubation time. The biophysical explanation for the unprecedented plasticity of PrP Sc remains to be determined.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.0608970103
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2006
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
