"At UK DRI at Cardiff we're exploring the function of genes involved in Alzheimer’s, Parkinson’s and Huntington’s disease. We hope to identify molecular targets that will lead to new drugs that can prevent or treat dementia. " Prof Julie Williams
UK DRI Centre Director
1. At a glance
Rapid advances in DNA technologies and computational biology are enabling scientists to identify more and more of the subtle DNA variations that can influence a person’s risk of developing different neurodegenerative diseases – or modify their severity – in combination with other genetic and environmental factors.
Scientists are using these genetic clues to piece together a better understanding of the biological mechanisms that contribute to dementia. This is revealing the underlying complexity of the systems involved, with disturbances to several processes helping to tip the balance from health to disease. The relevance of some is only just becoming apparent – for example, the recent identification of several immune-related risk genes has underlined the important role of the body’s immune system in Alzheimer’s disease.
Researchers at the UK DRI at Cardiff are now interrogating the host of genetic variations linked with neurodegenerative diseases including Alzheimer's disease, Parkinson's disease and Huntington's disease, to make new discoveries about disease processes. They are using experimental model systems along with a variety of cutting-edge experimental methods and equipment - such as the SMARTer ICELL8cx Single-Cell Automation System - to dissect the biology of many of these genes. Building on the team’s international reputation for complex data analyses, they are also developing and applying advanced computational approaches that are enabling them to make sense of huge datasets from complex experiments.
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2. Scientific goals
The strategy of the UK DRI at Cardiff builds upon its current research strengths in dementia genetics; immunology; computational analysis; cellular and whole system modelling and neuroimaging, to identify disease mechanisms and novel therapies for Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s diseases (HD) and other forms of dementia.
Previous work at the centre has highlighted the multifactorial nature of AD, PD and even HD – a monogenic disorder with significant gene modifiers. For example, genetic discoveries of rare or common variants/loci influencing AD illuminate its true complexity. Evidence shows that the 40 genome-wide loci associated with the disease are not random but support several pathways likely to be involved in the disease process, including immunity/inflammation, endocytosis, cholesterol transport, ubiquitination and amyloid beta processing. Genomic analyses further support the role of immunity/inflammation and specifically highlight the role of microglia in AD and astrocytes in PD – and so exploring these mechanisms is a strong component of the centre.
The researchers are now taking forward these genetic and genomic findings to the logical next step, which is to identify disease mechanisms and produce targets for preventative and modifying therapies. Drosophila modelling is important for testing and creating hypotheses at speed, which will be followed up in human stem cell models and in animal models where appropriate. In particular, human-based stem cells will play a vital role both in modelling disease complexity but also in providing better disease models for testing therapeutics.
Over the last ten years, researchers in Cardiff have developed an international reputation for complex data analysis. Data emanating from multi-omic/multi-tissue experiments will need sophisticated analytical approaches to identify the more complex patterns likely to underpin relationships. Therefore, the team is further increasing their strength in complex analytics, both in applying mathematical methods not currently used in the neurodegeneration field and in developing novel computational approaches tailored to research needs.
3. IPSC Platform to Model Alzheimer’s Disease Risk (IPMAR)
Launched in April 2021, the IPSC Platform to Model Alzheimer’s Disease Risk (IPMAR) is a major initiative led by UK DRI at Cardiff, which aims to become one of the largest cellular model resources available to study Alzheimer’s, helping researchers worldwide explore risk factors that contribute to development of the disease.
Alzheimer’s disease is a multifactorial and extremely complex condition. In the majority of cases, the risk of developing it is determined by thousands of small contributions from our genes, along with environmental factors such as lack of exercise. Researchers have been analysing huge genetic datasets to generate polygenic risk scores (PRS), which are a calculation of an individual’s overall risk for developing Alzheimer’s. Led by Prof Julie Williams, Centre Director from UK DRI at Cardiff, the IPMAR team plan to create and validate up to 60 induced pluripotent stem cell (iPSC) lines from people with high or low polygenic risk for Alzheimer’s. These iPSCs can be transformed into nearly any cell type in the body, such as neurons or microglia immune cells, and will be an invaluable resource for modelling and studying the complex biology that the disease presents.
Find out more about the IPMAR from the launch news article.
Within UK DRI
- Prof Bart De Strooper, UK DRI at UCL
- Prof Henrik Zetterberg, UK DRI at UCL
- Prof Sarah Tabrizi, UK DRI at UCL
- Prof Siddharthan Chandran, UK DRI at Edinburgh
- Dr Gabriel Balmus, UK DRI at Cambridge
UK DRI Co-investigator
Beyond UK DRI
- Dr Georgina Menzies, Cardiff University
- Prof Meng Li, Cardiff University
- Prof Gareth Howell, The Jackson Labs
- Prof Nick Allen, Cardiff University
- Dr Emyr Lloyd-Evans, Cardiff University
- Prof Frank Sengpiel, Cardiff University
- Prof Zheng Zhao, University of Southern California
- GlaxoSmithKline (GSK)
- Dementia Platforms UK (DPUK): implementation of genetic/phenotypic data analyses
- C-FoS/AD consortium
- Psychiatric Genomics Consortium (PCG)
- Genetic and Environmental Risk in Alzheimer's Disease (GERAD) consortium
- International Genomics of Alzheimer's Project (IGAP) consortium
- International Frontal Temporal Dementia Genomics Consortium (IFGC)
Risk genes, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, computational biology, model systems, functional genomics, polygenic risk scores, iPSC, neuroinflammation
Cas9, AAV technologies, PinT, EpiEffector, CRISPR screening, mouse models, iPSCs, siRNA screening, computational biology, machine learning (support vector machines (SVM), random forests and neural networks (NN)), GWAS, ChIP-seq, ATACseq, canonical correlations analyses, machine-learning approaches (Support Vector Machines, Artificial Neuronal Networks); statistical modelling, functional analysis (based on Gene Ontology enrichment), polygenic risk scores, MRI imaging (including susceptibility weighted imaging (SWI), micro-anisotropy (μFA), quantitative magnetic transfer imaging (qMT)), mouse models, iPS-derived microglia, murine synaptosome and synaptoneurosome isolation, confocal microscopy, Drosophila genetic screening, high-throughput image analysis, Drosophila, GCaMPs, live imaging of organelles, bioinformatics, in vivo 2-photon microglial imaging, transcriptomics, scRNAseq, human iPSCs, Takara ICell8cx single cell platform, iPSC LMX1a reporter line, CRISPR.