title: Hemin as a generic and potent protein misfolding inhibitor.
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.
authors.affiliation: School of Chemistry and Physics, The University of Adelaide, Adelaide, SA 5005, Australia.
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Discipline of Pharmacology, The University of Adelaide, Adelaide, SA 5005, Australia.
authors.forename: John A
authors.initials: JA
authors.lastname: Carver
authors.affiliation: School of Chemistry and Physics, The University of Adelaide, Adelaide, SA 5005, Australia.
authors.forename: Lam H
authors.initials: LH
authors.lastname: Ho
authors.affiliation: School of Chemistry and Physics, The University of Adelaide, Adelaide, SA 5005, Australia.
authors.forename: Abigail K
authors.initials: AK
authors.lastname: Elias
authors.affiliation: Research School of Chemistry, The Australian National University, Canberra, ACT 0200, Australia.
authors.forename: Ian F
authors.initials: IF
authors.lastname: Musgrave
authors.affiliation: School of Chemistry and Physics, The University of Adelaide, Adelaide, SA 5005, Australia. Electronic address: tara.pukala@adelaide.edu.au.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Pukala
mesh_terms: D000426:Alcohol Dehydrogenase / Q000378:metabolism; D000682:Amyloid / Q000378:metabolism* / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002364:Caseins / Q000737:chemistry / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D006427:Hemin / Q000378:metabolism*; D006801:Humans; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D066263:Protein Aggregation, Pathological / Q000378:metabolism; D017510:Protein Folding; D017433:Protein Structure, Secondary; D051844:alpha-Synuclein / Q000378:metabolism; D038222:gamma-Crystallins / Q000378:metabolism
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D002364:Caseins; D010446:Peptide Fragments; D051844:alpha-Synuclein; C075222:amyloid beta-protein (1-42); D038222:gamma-Crystallins; D006427:Hemin; D000426:Alcohol Dehydrogenase; D002374:Catalase
keywords: Amyloid fibrils; Cell toxicity; Hemin; Protein misfolding; γs-Crystallin