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体外和人体组织中过渡金属和肽表征的最新分析进展，以促进对帕金森病病理学的理解[埃弗雷特等人，纳米尺度，2018; Lermyte等人，细胞，2019，布鲁克斯等人，Angewandte Chemie，2020]。该项目直接建立在Bellingeri在2018/19年的MChem最后一年项目工作中的发现[Lermyte et al，Cells 2019 and conference presentations at ASMS 2019 and BMSS 2019]，并将涉及基尔大学沃里克化学工程学院医学实验室痕量金属之间的合作，以及在钻石光源同步加速器上拟议的实验工作。该项目的具体目的是确定聚集蛋白a-突触核蛋白的特性，特别是其金属结合特性，体外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病病理学中的作用的理解中的关键差距，提供有关这些聚集体引起的磁共振成像对比度的新信息，并为目前临床试验中的金属螯合药物的治疗策略提供信息。参考文献[布鲁克斯2020] J.布鲁克斯，J.埃弗雷特，F. Lermyte，V. Tjendana Tjhin，S. Banerjee，P.J. Sadler，P.B.奥康纳角Morris，N. Telling和J.F.科林伍德，通过软X射线光谱显微镜对脑中神经黑色素进行无标记纳米成像。应用化学国际版。2020年5月14日; 59（29）：11984-11991。[Lermyte 2019] Frederik Lermyte，James埃弗雷特，Jake布鲁克斯，Francesca Bellingeri，Kharmen Billimoria，Peter J. Sadler，Peter B.作者：奥康纳Telling，Joanna科林伍德，“新兴方法研究过渡金属对蛋白质病变的影响”，细胞2019年10月10日;8（10）PubMed PMID：31658742; [埃弗雷特2018] James埃弗雷特，Joanna F.科林伍德[通讯作者]，Vindy Tjendana-Tjhin，Jake布鲁克斯，Frederik Lermyte，Germán Plascia-Villa，Ian Hands-Portman，Jon多布森，乔治佩里和Neil D. Telling，“阿尔茨海默病受试者淀粉样斑块核心中亚铁和钙化合物的纳米同步加速器X射线形态分析”，Nanoscale，2018 v10，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