Academic responsible - Dr Joanna Collingwood
Our primary focus is imaging and quantifying transition metal ion distribution in the human brain, supporting progress in early detection and diagnosis for neurodegenerative disorders. We use a variety of analytical techniques, including high resolution MRI, synchrotron X-ray microfocus spectroscopy, and magnetometry to characterize the distribution and form of trace metals in tissues and protein aggregates. Please see our recent publications, most of which are open-access.
Trace Metals in Medicine Laboratory, build completed in 2011 and equipped for sample preparation and analysis. Resources include:
- Wet-lab with chemical safety cabinets, refrigerated centrifuge, balances, ultrapure water supply, and refrigeration equipment.
- Containment level 1 area with Class II biosafety cabinets, cryomicrotome sectioning for trace metals analysis in tissues, ultramicrotome sectioning, fluorescence light microscopy (inverted microscopy), and freeze drying.
- Cell culture resources (including incubator and fluorescence plate reader).
- MRI Probe (for imaging at 9.4 T): we have a state-of-the-art MR microscopy probe that utilizes the 400 MHz spectrometer in Millburn House, under the Science Cities Translational Medicine 2 Programme. It is presently configured for in-vitro work, and the coils are primarily volume coils for 1H imaging; we also have a surface coil, and a 19F volume coil for small samples (<5mm) .
Complementary facilities are available in the adjacent Microscopy and Analysis Laboratory, run by Martin Davis, is a School of Engineering resource providing a small materials analysis and imaging service. The laboratory is primarily run for the benefit of the School of Engineering staff and students; however, it also offers the same service to parties from other departments and from outside the University.Complementary resources include:
- Environmental SEM.
- Electron beam microprobe
Metal-ion-based neurodegeneration: enabling techniques for understanding, detection and treatment.
PI: Joanna Collingwood. Funder: EPSRC. 2013 - 2015
Summary: Many diseases of the human brain lead, over time, to degeneration of tissue and loss of function. By the time the disease is detected in an individual because of loss of function (whether cognitive or physical), extensive degeneration has in many instances already taken place. Reversing this degeneration presents an enormous challenge; the goal of this project is instead to focus on understanding factors that contribute to causing the degeneration, and to find ways of identifying the degeneration at an early stage in order to i) improve detection, and ii) offer new targets for effective treatment.
A common theme linking many neurodegenerative diseases such as Alzheimer's, Parkinson's, Huntington's, Motor Neurone Disease, and Multiple System Atrophy, is that changes in the regulation of certain trace metals, and/or the proteins responsible for binding and utilizing these metal elements, are apparent. This can include accumulation of certain elements, such as iron, in specific regions of the brain. Our hypothesis is that these changes are disease-specific, and if better understood, may provide windows of opportunity for improved detection and treatment.
Limiting factors affecting present work in this area include:
i) the challenge of extrapolating findings from simple experiments in the laboratory to the complexity of the biochemical environment in the brain;
ii) the challenge of accurate sensitive detection of trace metal elements in the brain - both for measurement in the living brain using clinical techniques, and for laboratory analysis of brain tissue.
In the proposed research, a combination of experiments and computer-based modelling will be undertaken, in order to describe, predict, and test mechanisms of trace metal regulation that are anticipated to be affected in some of these neurodegenerative disorders. The models will be constructed using what is already known from experimental work, including published data from other research groups. In turn, as predictions are made by the models developed in this project, experiments will be designed and performed to test the predictions and update the models accordingly.
Experiments to look at the interactions between metal-binding proteins and the trace metals that affect their aggregation, will be made more physiologically relevant by studying them in purpose-designed 'microfluidic' systems: experimental systems engineered to enable work with extremely small volumes (micro- or nanolitres) of sample. Microfluidic systems have three particular advantages in this context: i) they allow much smaller amounts of sample to be studied than would normally be the case, ii) they permit high-throughput testing of many experimental conditions for a single batch of protein which improves efficiency and reduces ambiguity in the results, and iii) the very small volumes and control of interfaces that can be achieved make it possible to mimic physiological conditions more accurately than has previously been possible.
Very sensitive analysis of trace metals in tissues will be achieved in experiments using UK synchrotron facilities. These provide extremely bright beams of X-rays that can be focussed to micron or sub-micron diameters for mapping. The beams excite natural fluorescence signal from specific elements such as iron, copper, and zinc, enabling patterns of deposition to be mapped for each element even for trace concentrations of just a few parts per million.
It is anticipated that the specific questions addressed in this project will help further our understanding of how iron affects the aggregation of a particular protein found in Lewy body pathology in Parkinson's disease, and will also enable progress in understanding how (and where) brain iron storage is affected in certain neurodegenerative disorders, to assess if there are sufficient differences for these diseases to be detected, and distinguished from each other, using Magnetic Resonance Imaging.
- M Heidari, D M Johnstone, B Bassett, R M Graham, A C G Chua, M J House, J F Collingwood, C Bettencourt, H Houlden, M Ryten, J K Olynyk, D Trinder and E A Milward for the UK Brain Expression Consortium (UKBEC) (2016) 'Brain iron accumulation affects myelin-related molecular systems implicated in a rare neurogenetic disease family with neuropsychiatric features'. Molecular Psychiatry, doi: 10.1038/mp.2015.192
- Bettencourt C, Forabosco P, Wiethoff S, Heidari M, Johnstone DM, Botía JA, Collingwood JF, Hardy J, Milward EA, Ryten M, Houlden H; UK Brain Expression Consortium (UKBEC), (2015) 'Gene co-expression networks shed light into diseases of brain iron accumulation', Neurobiol Dis. S0969-9961(15)30106-6. doi: 10.1016/j.nbd.2015.12.004
- J.F. Collingwood and M.R. Davidson (2014) 'The role of iron in neurodegenerative disorders: insights and opportunities with synchrotron light'. Frontiers in Pharmacology, accepted, in press.
- J.F. Collingwood, M.E. Finnegan, Z. Arya, J.-P. Hagen, S. Chen, A. Chowdhury, S. Wayte, E. Ngandwe, N. Visanji, J. Dobson, P.A. Gowland, L.-N. Hazrati, & C.E. Hutchinson, ‘MRI evaluation of the relationship between R2, R2*, and tissue iron in the human basal ganglia’, International Society for Magnetic Resonance in Medicine Annual Meeting (2014), Milan, Italy
- Everett, J., Cespedes, E., Shelford, L. R., Exley, C., Collingwood, J. F. , Dobson, J., van der Laan, G., Jenkins, C. A., Arenholz, E. ,Telling, N. D. (2014) 'Evidence of Redox-Active Iron Formation Following Aggregation of Ferrihydrite and the Alzheimer's Disease Peptide beta-Amyloid'. Inorganic Chemistry, DOI: 10.1021/ic402406gJ.
- Everett, E. Céspedes, L.R. Shelford, C. Exley, J.F. Collingwood, J. Dobson, G. van der Laan, C.A. Jenkins, E. Arenholz and N.D. Telling (2014) 'Ferrous iron formation following the co-aggregation of ferric iron and the Alzheimerʼs disease peptide β-amyloid (1-42)', Journal of the Royal Society Interface, 11(95):20140165. doi: 10.1098/rsif.2014.0165
- Visanji NP, Collingwood JF, Finnegan ME, Tandon A, House E, Hazrati LN. (2013) 'Iron Deficiency in Parkinsonism: Region-Specific Iron Dysregulation in Parkinson's Disease and Multiple System Atrophy'. J Parkinsons Dis. PMID: 24113558