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

该项目将扩展和应用在体外和人体组织中表征过渡金属和多肽的最新分析进展，以促进对帕金森氏病病理的理解[Everett等人，Nanscalale，2018；Lermyte等人，Cells，2019，Brooks等人，Angewandte Chemie，2020]。该项目直接基于Bellingeri在2018/19年MChem最后一年项目工作中的发现[Lermyte等人，Cells 2019以及ASMS 2019和BMS 2019上的会议演示]，并将涉及基尔大学华威化学工程学院医学实验室与钻石光源同步加速器拟议的实验工作之间的合作。这个项目的具体目标是确定聚集蛋白a-突触核蛋白的性质，特别是它在体外与金属结合的性质，以及它在人脑中形成聚集体的位置。这项工作将解决目前对这种蛋白质在帕金森氏病病理中的核心作用的理解中的关键空白，提供有关这些聚集体引起的磁共振成像对比的新信息，并为目前正在临床试验的金属螯合药物的治疗策略提供信息。参考文献[Brooks 2020]J.Brooks，J.Everett，F.Lermyte，V.Tjendana Tjhin，S.Banerjee，P.J.Sadler，P.B.O‘Connor，C.Morris，N.Tell和J.F.Collingwood，通过软X射线光谱显微镜对大脑中的神经黑素进行无标记纳米成像。Angewandte化学国际版。2020年5月14日；59(29)：11984-11991。[2019年]弗雷德里克·勒米特、詹姆斯·埃弗雷特、杰克·布鲁克斯、弗朗西丝卡·贝林格里、哈尔门·比利莫里亚、彼得·J·萨德勒、彼得·B·奥康纳、尼尔·D·泰林、乔安娜·科林伍德，《调查过渡金属对蛋白质病的影响的新方法》，Cells 2019年10月10日；8(10)PubMed PMID：31658742；[Everett 2018]James Everett，Joanna F.Collingwood[通讯作者]，Vindy Tjendana-Tjhin，杰克·布鲁克斯，Frederk Lermyte，Germán Plascencia-Villa，Ian Hands-Portman，Jon Dobson，George Perry和Neil D.Tell，《纳米同步加速器X射线在阿尔茨海默病患者淀粉样斑块核心中铁和钙化合物的形态形成》，NanScale，2018V10，p11782-11796，https://doi.org/10.1039/C7NR06794A

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