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Hemin as a generic and potent protein misfolding inhibitor
Authors:Yanqin Liu  John A Carver  Lam H Ho  Abigail K Elias  Ian F Musgrave  Tara L Pukala
Institution:1. School of Chemistry and Physics, The University of Adelaide, Adelaide, SA 5005, Australia;2. Discipline of Pharmacology, The University of Adelaide, Adelaide, SA 5005, Australia;3. Research School of Chemistry, The Australian National University, Canberra, ACT 0200, Australia
Abstract:Protein misfolding causes serious biological malfunction, resulting in diseases including Alzheimer’s disease, Parkinson’s disease and cataract. Molecules which inhibit protein misfolding are a promising avenue to explore as therapeutics for the treatment of these diseases. In the present study, thioflavin T fluorescence and transmission electron microscopy experiments demonstrated that hemin prevents amyloid fibril formation of kappa-casein, amyloid beta peptide and α-synuclein by blocking β-sheet structure assembly which is essential in fibril aggregation. Further, inhibition of fibril formation by hemin significantly reduces the cytotoxicity caused by fibrillar amyloid beta peptide in vitro. Interestingly, hemin degrades partially formed amyloid fibrils and prevents further aggregation to mature fibrils. Light scattering assay results revealed that hemin also prevents protein amorphous aggregation of alcohol dehydrogenase, catalase and γs-crystallin. In summary, hemin is a potent agent which generically stabilises proteins against aggregation, and has potential as a key molecule for the development of therapeutics for protein misfolding diseases.
Keywords:Aβ42  amyloid-beta peptide 1-42  AD  Alzheimer&rsquo  s disease  ADH  alcohol dehydrogenase  αS  alpha-synuclein  CD  circular dichroism  DTT  1  4-dithiothreitol  RCM-κ-CN  reduced and carboxymethylated kappa-casein  MTT  3-[4  5-dimethylthiazol-2-yl]-2  5-diphenyltetrazolium bromide  PD  Parkinson&rsquo  s disease  TEM  transmission electron microscopy  ThT  thioflavin T
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