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Emerging approaches to investigate the influence of transition metals in the proteinopathies

DOI: 10.3390/cells8101231 DOI Help

Authors: Frederik Lermyte (University of Warwick) , James Everett (University of Warwick; Keele University) , Jake Brooks (University of Warwick) , Francesca Bellingeri (University of Warwick) , Kharmen Billimoria (University of Warwick) , Peter J. Sadler (University of Warwick) , Peter B. O’connor (University of Warwick) , Neil Telling (Keele University) , Joanna F. Collingwood (Warwick University; University of Florida)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cells , VOL 8

State: Published (Approved)
Published: October 2019
Diamond Proposal Number(s): 15854 , 19779

Open Access Open Access

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 β (1–42) or α-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 α-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.

Journal Keywords: Alzheimer’s disease; Parkinson’s disease; amyloid β; α-synuclein; copper; iron; mass spectrometry; electrospray ionization; x-ray; spectromicroscopy

Subject Areas: Chemistry, Biology and Bio-materials, Technique Development


Instruments: I18-Microfocus Spectroscopy

Documents:
cells-08-01231.pdf