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Lermyte, F, Everett, J, Brooks, J, Bellingeri, F, Billimoria, K, Sadler, PJ, O’Connor, PB, Telling, ND ORCID: https://orcid.org/0000-0002-2683-5546 and Collingwood, JF (2019) Emerging Approaches to Investigate the Influence of Transition Metals in the Proteinopathies. Cells, 8 (10).

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Abstract

Transition metals have essential roles in brain structure and function, and are associated with pathological processes in neurodegenerative disorders classed as proteinopathies. Synchrotron X-ray techniques, coupled with ultrahigh-resolution mass spectrometry, have been applied to study iron and copper interactions with amyloid beta; or alpha-synuclein. Ex vivo tissue and in vitro systems were investigated, showing the capability to identify metal oxidation states, probe local chemical environments, and localize metal-peptide binding sites. Synchrotron experiments showed that the chemical reduction of ferric (Fe3+) iron and cupric (Cu2+) copper can occur in vitro after incubating each metal in the presence of Aβ for one week, and to a lesser extent for ferric iron incubated with α-syn. Nanoscale chemical speciation mapping of Aβ-Fe complexes revealed a spatial heterogeneity in chemical reduction of iron within individual aggregates. Mass spectrometry allowed the determination of the highest-affinity binding region in all four metal-biomolecule complexes. Iron and copper were coordinated by the same N-terminal region of Aβ, likely through histidine residues. Fe3+ bound to a C-terminal region of α-syn, rich in aspartic and glutamic acid residues, and Cu2+ to the N-terminal region of alpha;-syn. Elucidating the biochemistry of these metal-biomolecule complexes and identifying drivers of chemical reduction processes for which there is evidence ex-vivo, are critical to the advanced understanding of disease aetiology.

Item Type: Article
Additional Information: This is the final published version of the article (version of record). It first appeared online via MDPI at https://www.mdpi.com/2073-4409/8/10/1231 - please refer to any applicable terms of use of the publisher.
Uncontrolled Keywords: Alzheimer’s disease, Parkinson’s disease, amyloid, Ó synuclein, copper, iron, mass spectrometry, electrospray ionization, X-ray, spectromicroscopy
Subjects: R Medicine > RS Pharmacy and materia medica
Divisions: Faculty of Medicine and Health Sciences > School of Pharmacy and Bioengineering
Depositing User: Symplectic
Date Deposited: 22 Oct 2019 15:53
Last Modified: 25 Feb 2021 15:47
URI: https://eprints.keele.ac.uk/id/eprint/7061

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