Metal-ion-based neurodegeneration: enabling techniques for understanding, detection, and treatment

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.

The research will advance our understanding of the mechanisms of metal-ion-based neurodegeneration. It is anticipated that the research will affect clinical tools for detection and improved differential diagnosis of neurodegenerative disease on a 5 - 10 year timescale; in the shorter term there is scope for the research to affect drug development strategies for mediating metal-ion-based neurotoxicity. There is a pressing need for both: we do not presently have effective treatments for neurodegenerative disorders, and specific diagnosis of prevalent forms of neurodegeneration remains extremely difficult; diagnosis is often only confirmed at autopsy. The two challenges are interlinked, as without clear means to accurately identify patients in the early stages of a neurodegenerative disease, there is a limit on the effectiveness of the clinical trials that can be undertaken to develop appropriate therapies.

Research into the role of metal ions in neurodegenerative disorders is often limited to descriptive observations and speculative conclusions. While interactions and mechanisms may be robustly tested in-vitro, their relevance to in-vivo conditions can be hard to establish. Combining quantitative and systems approaches to this field provides great scope to establish and test models of metal-based neurodegeneration, where model development will be informed, tested, and refined with experimental data on an iterative basis.

The project will have significant impact on biomedical engineering research capacity at the host institution (University of Warwick), increasing the scope of the experimental and systems projects that can be undertaken at postgraduate, postdoctoral, and inter-departmental level. It will also provide the foundations for joint projects involving colleagues from other institutions, including other universities in the Midlands, and from the healthcare sector including University Hospitals Coventry and Warwickshire. Internationally, the work will provide opportunities to reinforce and expand collaborations with colleagues in the USA, Canada, Europe, and Australia.

The public engagement element of the project will contribute to social awareness of biomedical engineering as a discipline, to an understanding of how the UK large facilities can be used to advance healthcare-related research, and to awareness of the significant unmet challenges in the field of neurodegenerative disease.

Dissemination of the research findings via peer reviewed journals and conference presentations, and via publications with broader impact such as the Chemistry and Industry article authored by the PI in 2010, and the Nature Outlooks article featuring the PI's research, also in 2010. These forms of dissemination are important for reaching professionals from many sectors in addition to academic specialists in the field.

The medical technology sector, encompassing work in both diagnostics and therapeutics, is experiencing strong growth both in the UK, and worldwide, compared to the majority of other industry sectors. Demographic shifts in many countries throughout the world are leading to an increased proportion of older people, and therefore the proportion of the population developing neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. The growth in the highly innovative medical technology sector is important for the UK economy, incorporating approximately 4,000 companies, over 90,000 employees, and turnover approaching £20bn, according to UK government (BIS) statistics from December 2010. Research enabling progress in this sector is therefore timely, and stands to benefit the economic development of the UK.