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

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Lermyte, Frederik, Everett, James, Brooks, Jake, Bellingeri, Francesca, Billimoria, Kharmen, Sadler, Peter J., O’Connor, Peter B., Telling, Neil D. and Collingwood, Joanna F. (2019) Emerging approaches to investigate the influence of transition metals in the proteinopathies. Cells, 8 (10). 1231. doi:10.3390/cells8101231 ISSN 2073-4409.

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Official URL: http://dx.doi.org/10.3390/cells8101231

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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 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.

Item Type: Journal Article
Subjects: Q Science > QC Physics
Q Science > QD Chemistry
Q Science > QP Physiology
R Medicine > RC Internal medicine
Divisions: Faculty of Science, Engineering and Medicine > Science > Chemistry
Faculty of Science, Engineering and Medicine > Engineering > Engineering
Library of Congress Subject Headings (LCSH): Mass spectrometry, Electrospray ionization mass spectrometry, Transition metals, Transition metals -- Health aspects, Alzheimer's disease, Alzheimer's disease -- Molecular aspects, Parkinson's disease, Parkinson's disease -- Molecular aspects, Metals in the body
Journal or Publication Title: Cells
Publisher: MDPI AG
ISSN: 2073-4409
Official Date: 10 October 2019
Dates:
DateEvent
10 October 2019Published
6 October 2019Accepted
Volume: 8
Number: 10
Article Number: 1231
DOI: 10.3390/cells8101231
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access (Creative Commons)
Date of first compliant deposit: 27 November 2019
Date of first compliant Open Access: 29 November 2019
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
EP/N033191/1[EPSRC] Engineering and Physical Sciences Research Councilhttp://dx.doi.org/10.13039/501100000266
EP/N033140/1[EPSRC] Engineering and Physical Sciences Research Councilhttp://dx.doi.org/10.13039/501100000266
Doctoral training award[EPSRC] Engineering and Physical Sciences Research Councilhttp://dx.doi.org/10.13039/501100000266
P021875/1[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
UNSPECIFIEDDiamond Light Sourcehttp://dx.doi.org/10.13039/100011889
UNSPECIFIEDPaul Scherrer Instituthttp://dx.doi.org/10.13039/501100004219

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