期刊
FASEB JOURNAL
卷 24, 期 9, 页码 3536-3543出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.09-150987
关键词
prion protein; thermodynamic stability; neurotoxicity; crowded environment; oligomerization
资金
- National Key Scientific Program (973)-Nanoscience and Nanotechnology [2006CB933100]
- National Natural Science Foundation of China [30970150]
- Program for New Century Excellent Talents in University [NCET-06-0620]
- Program for Changjiang Scholars and Innovative Research Team in University [IRT 0745]
Prion diseases are fatal neurodegenerative disorders and are linked with the conversion of the cellular isoform of the prion protein (PrPC) into the abnormal beta-sheet-rich isoform. It is widely accepted that the soluble oligomers of beta-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 beta-oligomers. By recording circular dichroism spectra and performing a size-exclusion HPLC assay, we found that the conformation of the recombinant human prion protein (rPrP(C)) was converted from an alpha-helical conformation into beta-sheet oligomers under a macromolecular crowding condition. The soluble beta-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 beta-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 beta-oligomers in prion diseases.-Huang, L., Jin, R., Li, J., Luo, K., Huang, T., Wu, D., Wang, W., Chen, R., Xiao, G. Macromolecular crowding converts the human recombinant PrPC to the soluble neurotoxic beta-oligomers. FASEB J. 24, 3536-3543 (2010). www.fasebj.org
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