Hemin as a generic and potent protein misfolding inhibitor

Abstract

After the embargo period via non-commercial hosting platforms such as their institutional repository  via commercial sites with which Elsevier has an agreement In all cases accepted manuscripts should: link to the formal publication via its DOI  bear a CC-BY-NC-ND license -this is easy to do, click here to find out how  if aggregated with other manuscripts, for example in a repository or other site, be shared in alignment with our hosting policy  not be added to or enhanced in any way to appear more like, or to substitute for, the published journal article AbstractProtein 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. Highlights Hemin prevents Aβ42, α-synuclein, and RCM-κ-casein forming amyloid fibrils  Hemin inhibits the β-sheet structure formation of Aβ42  Hemin reduces the cell toxicity caused by fibrillar Aβ42  Hemin dissociates partially formed Aβ42 fibrils  Hemin prevents amorphous aggregation by ADH, catalase and γs-crystallin

Rosmarinic Acid Restores Complete Transparency of Sonicated Human Cataract Ex Vivo and Delays Cataract Formation In Vivo

“…The effect of various systemic 10 – 13 and topical 14 – 17 pharmacological agents on cataract-associated protein aggregation has been investigated in recent years. Several in vitro studies have used different purified crystallin proteins and have shown that their aggregation is inhibited by selected small molecules 13 , 39 – 41 . Other studies utilized whole or homogenized lenses derived from various animal models, in an attempt to better mimic the pathological conditions in the living human eye 11 , 42 , 43 .…”

Ion Mobility—Mass Spectrometry-Based Screening for Inhibition of α-Synuclein Aggregation

“…Interestingly, hemin and hematin, which are both ironcontaining porphyrins differing only in the presence of chloride or hydroxide ligand respectively, have substantially different inhibitory efficacy. Since hemin is a degradation product of haemoglobin 46 which is also thought to have an influence on amyloid formation, 47,48 and is found to be a potent generic protein misfolding inhibitor, 49 further study is warranted to investigate the interaction between hemin, haemoglobin, iron and synuclein.…”

A Metalloporphyrin-Peptide Conjugate as an Effective Inhibitor of Amyloid-β Peptide Fibrillation and Cytotoxicity

“…In this respect, recent experimental work uses porphyrins and conjugates thereof as suppressors of β‐amyloid aggregation and cytotoxicity . Porphyrins have been used as pioneering agents not only for diagnostic imaging, but also for therapy .…”