Inhibition of fibril formation and toxicity of a fragment of alpha-synuclein by an N-methylated peptide analogue.
Alpha-synuclein has been linked to amyloidogenesis in Parkinson's disease and other neurodegenerative disorders. We have previously shown that a peptide comprising residues 68-78 of alpha-synuclein is the minimum fragment that, like alpha-synuclein itself, forms amyloid fibrils and exhibits toxicity towards cells in culture. Hughes et al. [J. Biol. Chem. 275 (2000) 25109] showed that an N-methylated derivative of Abeta(25-35) inhibited the formation of fibrils by Abeta(25-35) and reduced its toxicity. We have now extended this concept to an amyloidogenic alpha-synuclein-based peptide. Alpha-synuclein(68-78), N-methylated at G1y73, was compared to non-methylated peptide. Whereas alpha-synuclein(68-78) formed fibrils and was toxic to cells, the N-methylated analogue had neither of these properties. Moreover, an equimolar mixture of the non-methylated and methylated peptides formed very few fibrils and toxicity was markedly reduced.
Bodles
Angela M
AM
Centre for Peptide and Protein Engineering, School of Biology and Biochemistry, The Queen's University of Belfast, Medical Biology Centre, Belfast BT9 7BL, UK.
El-Agnaf
Omar M A
OM
Greer
Brett
B
Guthrie
David J S
DJ
Irvine
G Brent
GB
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D009419:Nerve Tissue Proteins / Q000633:toxicity*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000633:toxicity*; D058225:Plaque, Amyloid / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D051843:Synucleins; D051844:alpha-Synuclein
D016229:Amyloid beta-Peptides; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C497606:Snca protein, rat; D051843:Synucleins; D051844:alpha-Synuclein; C074636:amyloid beta-protein (25-35)