Tetracycline affects abnormal properties of synthetic PrP peptides and PrP(Sc) in vitro.

Abstract

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 beta-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 Leu(125) of PrP 106-126. These properties make tetracycline a prototype of compounds with the potential of inactivating the pathogenic forms of PrP.

• Authors: F Tagliavini, G Forloni, L Colombo, G Rossi, L Girola, B Canciani, N Angeretti, L Giampaolo, E Peressini, T Awan, L De Gioia, E Ragg, O Bugiani, M Salmona
• Journal: Journal of molecular biology (J Mol Biol) Vol. 300 Issue 5 Pg. 1309-22 (Jul 28 2000) ISSN: 0022-2836 [Print] Netherlands
• PMID: 10903871 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2000 Academic Press.

Chemical References

• Neuroprotective Agents
• Peptide Fragments
• PrPSc Proteins
• Prions
• prion protein (106-126)
• Endopeptidase K
• Tetracycline

Topics

• Amino Acid Sequence
• Animals
• Astrocytes (drug effects, pathology)
• Binding Sites
• Brain (metabolism, pathology)
• Cell Division (drug effects)
• Cell Survival (drug effects)
• Cells, Cultured
• Creutzfeldt-Jakob Syndrome (drug therapy, metabolism, pathology)
• Endopeptidase K (metabolism)
• Humans
• Magnetic Resonance Spectroscopy
• Molecular Sequence Data
• Neurons (drug effects, pathology)
• Neuroprotective Agents (chemistry, metabolism, pharmacology, therapeutic use)
• Peptide Fragments (chemistry, metabolism, toxicity, ultrastructure)
• Plaque, Amyloid (chemistry, metabolism, ultrastructure)
• PrPSc Proteins (chemistry, metabolism, toxicity, ultrastructure)
• Prions (chemistry, metabolism, toxicity, ultrastructure)
• Protein Binding (drug effects)
• Protein Conformation (drug effects)
• Rats
• Solubility (drug effects)
• Tetracycline (chemistry, metabolism, pharmacology, therapeutic use)