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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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WRAP-emerging-approaches-investigate-influence-transition-metals-proteinopathies-Collingwood-2019.pdf - Published Version - Requires a PDF viewer. Available under License Creative Commons Attribution 4.0. Download (6Mb) | Preview |
Official URL: http://dx.doi.org/10.3390/cells8101231
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 | |||||||||||||||||||||
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| Subjects: | Q Science > QC Physics Q Science > QD Chemistry Q Science > QP Physiology R Medicine > RC Internal medicine |
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| Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry Faculty of Science, Engineering and Medicine > Engineering > Engineering |
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| 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: |
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| 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: |
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