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- Title
Macromolecular crowding converts the human recombinant PrP<sup>C</sup> to the soluble neurotoxic β-oligomers.
- Authors
Liqin Huang; Rui Jin; Jiarui Li; Kan Luo; Tao Huang; Di Wu; Wenxi Wang; Gengfu Xiao; Rui Chen
- Abstract
Prion diseases are fatal neurodegenerative disorders and are linked with the conversion of the cellular isoform of the prion protein (PrPC) into the abnormal β-sheet-rich isoform. It is widely accepted that the soluble oligomers of β-PrP are neurotoxic and that they are more pathologically significant. To unravel the molecular mechanism under the conversion process, it is critical to identify the factors that can promote the conversion from PrPC to the-oligomers. By recording circular dichroism spectra and performing a size-exclusion HPLC assay, we found that the conformation of the recombinant human prion protein (rPrPC) was converted from an-helical conformation into-sheet oligomers under a macromolecular crowding condition. The soluble-oligomers of rPrP were resistant to proteinase K digestion and could bind to the dyes thioflavin T and 8-anilino-1-naphthalene sulfonate. Furthermore, by the 3-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay, we showed that the soluble-oligomers were neurotoxic. These results suggest that macromolecular crowding, which has not been considered before, is a key intracellular factor in the formation of soluble neurotoxic-oligomers in prion diseases.
- Subjects
PRION diseases; THERMODYNAMICS; NEUROTOXICOLOGY; OLIGOMERS; NEURODEGENERATION
- Publication
FASEB Journal, 2010, Vol 24, Issue 9, p3536
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.09-150987