Alpha-synuclein and its interplay with metals in Parkinson's disease 1=Chemical reaction dynamics and mechanisms 2=Healthcare technologies

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This project will extend and apply recent analytical advances in the characterization of transition metals and peptides in-vitro and in human tissue, to advance understanding of Parkinson's disease pathology [Everett et al, Nanoscale, 2018; Lermyte et al, Cells, 2019, Brooks et al, Angewandte Chemie, 2020]. The project builds directly on Bellingeri's findings in her MChem final year project work in 2018/19 [Lermyte et al, Cells 2019 and conference presentations at ASMS 2019 and BMSS 2019], and will involve collaboration between the Trace Metals in Medicine Laboratory in the School of Engineering, Warwick Chemistry, Keele University, and proposed experimental work at the Diamond Light Source synchrotron. The specific aim of this project is to determine the properties of the aggregating protein a-synuclein, especially its metal binding properties, in-vitro and where it forms aggregates in the human brain. This work will address key gaps in current understanding of the role of this protein central to Parkinson's disease pathology, provide new information about the contrast in magnetic resonance imaging arises from these aggregates, and inform therapeutic strategies with metal chelating drugs currently in clinical trials. REFERENCES [Brooks 2020] J. Brooks, J. Everett, F. Lermyte, V. Tjendana Tjhin, S. Banerjee, P.J. Sadler, P.B. O'Connor, C. Morris, N. Telling and J.F. Collingwood, Label-Free Nanoimaging of Neuromelanin in the Brain by Soft X-ray Spectromicroscopy. Angewandte Chemie International Edition. 2020 May 14; 59(29):11984-11991. [Lermyte 2019] Frederik Lermyte, James Everett, Jake Brooks, Francesca Bellingeri, Kharmen Billimoria, Peter J. Sadler, Peter B. O'Connor, Neil D. Telling, Joanna Collingwood, 'Emerging approaches to investigate the influence of transition metals in the proteinopathies', Cells 2019 Oct 10;8(10)PubMed PMID: 31658742; [Everett 2018] James Everett, Joanna F. Collingwood [corresponding author], Vindy Tjendana-Tjhin, Jake Brooks, Frederik Lermyte, Germán Plascencia-Villa, Ian Hands-Portman, Jon Dobson, George Perry and Neil D. Telling, 'Nanoscale synchrotron X-ray speciation of ferrous iron and calcium compounds in amyloid plaque cores from Alzheimer's disease subjects', Nanoscale, 2018 v10, p11782-11796, https://doi.org/10.1039/C7NR06794A