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Emerging Approaches to Investigate the Influence of Transition Metals in the Proteinopathies

Telling; Everett, James

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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.

Acceptance Date Oct 6, 2019
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

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