NR ALIK
AU Tagliavini,F.; Forloni,G.; Colombo,L.; Rossi,G.; Girola,L.; Canciani,B.; Angeretti,N.; Giampaolo,L.; Peressini,E.; Awan,T.; de Gioia,L.; Ragg,E.; Bugiani,O.; Salmona,M.
TI Tetracycline affects abnormal properties of synthetic PrP peptides and PrPsc in vitro
QU Journal of Molecular Biology 2000 Jul 28; 300(5): 1309-22
PT journal article
AB Prion diseases are characterized by the accumulation of altered forms of the prion protein (termed PrPsc) in the brain. Unlike the normal protein, PrPsc 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 PrPsc 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.
MH Amino Acid Sequence; Animal; 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; Human; Magnetic Resonance Spectroscopy; Molecular Sequence Data; Neurons/drug effects/pathology; Neuroprotective Agents/chemistry/metabolism/pharmacology/therapeutic use; Peptide Fragments/chemistry/metabolism/toxicity/ultrastructure; PrPsc Proteins/*chemistry/*metabolism/toxicity/ultrastructure; Prions/*chemistry/metabolism/toxicity/ultrastructure; Protein Binding/drug effects; Protein Conformation/drug effects; Rats; Senile Plaques/chemistry/metabolism/ultrastructure; Solubility/drug effects; Support, Non-U.S. Gov't; Tetracycline/chemistry/metabolism/*pharmacology/therapeutic use
AD Istituto Nazionale Neurologico Carlo Besta, Via Celoria 11, Milano, 20133, Italy.
SP englisch
PO England