Neil Telling n.d.telling@keele.ac.uk
Emerging Approaches to Investigate the Influence of Transition Metals in the Proteinopathies
Telling; Everett, James
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.
Acceptance Date | Oct 6, 2019 |
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Publication Date | Oct 10, 2019 |
Publicly Available Date | Mar 28, 2024 |
Journal | Cells |
Publisher | MDPI |
DOI | https://doi.org/10.3390/cells8101231 |
Keywords | Alzheimer’s disease, Parkinson’s disease, amyloid, Ó synuclein, copper, iron, mass spectrometry, electrospray ionization, X-ray, spectromicroscopy |
Publisher URL | https://www.mdpi.com/2073-4409/8/10/1231 |
Files
cells-08-01231-v2.pdf
(6.8 Mb)
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Publisher Licence URL
https://creativecommons.org/licenses/by/4.0/
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