Tetracycline affects abnormal properties of synthetic PrP peptides and PrP^Sc in vitro

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• 作者：Tagliavini ; Fabrizio ; Forloni ; Gianluigi ; Colombo ; Laura ; Rossi ; Giacomina ; Girola ; Laura ; et. al.
• 关键词：amyloidogenesis ; cell cultures ; NMR spectroscopy ; PrP peptides ; tetracycline ; BSE ; bovine spongiform encephalopathy ; CJD ; Creutzfeldt-Jakob disease ; vCJD ; new variant of Creutzfeldt-Jakob disease ; GSS ; Gerstmann-Strä ; ussler-Scheinker disease ; PrP ; pri
• 刊名：Journal of Molecular Biology
• 出版年：2000
• 出版时间：July 28, 2000
• 年：2000
• 卷：300
• 期：5
• 页码：1309-1322
• 全文大小：549 K

文摘

Prion diseases are characterized by the accumulation of altered forms of the prion protein (termed PrP^Sc) in the brain. Unlike the normal protein, PrP^Sc isoforms have a high content of β-sheet secondary structure, are protease-resistant, and form insoluble aggregates and amyloid fibrils. Evidence indicates that they are responsible for neuropathological changes (i.e. nerve cell degeneration and glial cell activation) and transmissibility of the disease process. Here, we show that the antibiotic tetracycline: (i) binds to amyloid fibrils generated by synthetic peptides corresponding to residues 106–126 and 82–146 of human PrP; (ii) hinders assembly of these peptides into amyloid fibrils; (iii) reverts the protease resistance of PrP peptide aggregates and PrP^Sc extracted from brain tissue of patients with Creutzfeldt-Jakob disease; (iv) prevents neuronal death and astrocyte proliferation induced by PrP peptides in vitro. NMR spectroscopy revealed several through-space interactions between aromatic protons of tetracycline and side-chain protons of Ala_117–119, Val_121–122 and Leu₁₂₅ of PrP 106–126. These properties make tetracycline a prototype of compounds with the potential of inactivating the pathogenic forms of PrP.