(MRC DTP) Multi-omic analysis of the human brain in dementia caused by Parkinson’s disease

No one can be in any doubt that dementia is a health and social care priority in terms of the numbers of people affected, and the impact on the individual, their carers and families, and society. There are, however no available disease-modifying therapies that can prevent or reverse any of the 7 main ageing-related dementias. Parkinson’s disease (PD) is one of these neurodegenerative diseases that lead to or cause dementia: PD-evoked dementia (1-5).

Phenotypes of complex diseases usually result from the interplay of several processes. In proof-of-principle studies, our team has developed a multi-dimensional methodology that we are using to analyse post-mortem human brain: so far, we have used it to perform in-depth studies of Alzheimer’s (AD) and Huntington’s (HD) diseases – both complex disorders of uncertain mechanism. Both AD and HD display brain region-specific molecular perturbations that display gradients in severity that reflect those in neuropathological and imaging signals from these diseases. Our preparatory studies have disclosed major previously unknown defects in AD and HD, including unexpected molecular linkages between these apparently distinct dementias. We expect that this will prove also to be the case in Parkinson’s disease with dementia.

The aims are:
(i) to derive robust chemical signals linked to neurodegeneration in brain tissue from patients who died with manifest or premanifest PD-evoked dementia
(ii) to discover/define specific molecular processes that are likely causative of disease.

These findings will yield a new way of finding a first-in-class treatments for PD-evoked dementia. Tissue for these studies will be sourced from the UK Brain Bank Network (UKBBN: www.mrc.ac.uk/research/facilities-and-resources-for-researchers/brain-banks/). Expected outcomes are based on our ongoing analysis of AD and HD: in each, our analysis has identified important new disease mechanisms that are evidently potential drug targets.

The methodology comprises: dissection of anatomically-defined brain regions (Dimension 1); metallomic analysis of brain (Dimension 2); metabolomics (Dimensions 3, 4); proteomics (Dimension 5); and target identification/localization (Dimension 6). Our recent publications, as listed above, provide worked examples of the application of these analytical methods to investigate novel disease mechanisms in the human brain in AD and HD.

By linking these data to evidence from behaviour, imaging and neuropathology, the student should expect to generate improved understanding of PD dementia mechanisms and characterise new targets for development of disease-modifying therapies.

CADET, the laboratories where main programme will be performed: http://cadetmanchester.org/
Professor Garth Cooper: principal supervisor who is expert in the metabolic basis and experimental therapeutics of chronic diseases such as dementia and diabetes: http://www.manchester.ac.uk/research/garth.cooper/
Dr Richard Unwin: co-supervisor who is expert in the multi-omic analysis of complex diseases: http://www.manchester.ac.uk/research/r.unwin/
Prof Nigel Hooper: co-supervisor, head of dementia research in Manchester and expert in molecular cell biology of dementia:http://www.manchester.ac.uk/research/nigel.hooper/
Dr Federico Roncaroli: co-supervisor who is expert in the molecular and clinical pathology of dementia: http://www.manchester.ac.uk/research/federico.roncaroli/