Research themes

Bringing together researchers to address major scientific questions

At the UK DRI, we study a range of neurodegenerative disorders that cause dementia. Many of them share fundamental disease mechanisms and characteristics, and greater understanding gained in one can often benefit others. To ensure we capitalise on diverse expertise, approaches and perspectives, we have established cross-centre themes that bring together researchers to address the major scientific questions that remain in these key topic areas for dementia.

Each theme has a scientific and administrative lead, whose role is to unite researchers and promote collaboration through sharing of knowledge, ideas, resources, best practice and data. Several events take place throughout the year including strategic meetings, workshops and symposia. Early career researchers from the themes organise dedicated activities via steering groups, such as webinar and networking events.

The themes are also a fantastic opportunity to link up with other organisations who share similar research interests. We’ve been thrilled to host collaborative symposia with networks at Dementias Platform UK (DPUK).

Find out more about research themes at the UK DRI in this Q&A with Research Theme Project Manager, Dr Sarmi Sri.

Our current research themes

DNA Repair

Scientific theme co-leads: Prof Vincent Dion (UK DRI at Cardiff) & Dr Gabriel Balmus (UK DRI at Cambridge)
Research theme project manager: Dr Ruby Wallis (UK DRI Central Team)

DNA repair mechanisms are crucial to protect the integrity of the genome by identifying and correcting damage. This capacity for repair is thought to decline as we age, contributing to an accumulation of DNA damage. Growing evidence shows genes involved in DNA repair are associated with several neurodegenerative diseases.

The DNA Repair theme is exploring how DNA repair contributes to neurodegeneration and finding ways to target these DNA repair pathways for therapeutics.

Among the initial areas of focus are Huntington’s disease and repeat expansion disorders, where we:

- address how somatic instability occurs

- investigate the progressive deregulation of DNA repair capacity during ageing

- uncover the emerging interaction between inflammation and DNA repair, and how it may contribute to neurodegeneration

We aim to take advantage of a greater understanding of these mechanisms to develop treatments directed at reducing repeat expansion or inducing repeat contractions. A major long-term area of interest is to find commonalities with neurodegenerative diseases outside the expanded repeat disorders.

Find out more about the DNA repair theme in this Q&A article with theme co-leads Prof Dion and Dr Balmus
Neuroimmune Interactions

Scientific theme co-leads: Dr Soyon Hong (UK DRI at UCL) & Dr Will McEwan (UK DRI at Cambridge)
Research theme project manager: Dr Sarmi Sri (UK DRI Central Team)

Our immune system plays a vital role in supporting our brain to function properly and, crucially, protect it from disease. However, as we age or present with chronic illness, the immune system’s abilities wane or can become dysfunctional. This not only impacts normal processes and mechanisms, but can itself cause further harm. There is growing evidence that brain’s immune system is an important driver of dementia, accelerating the neurodegeneration seen in the diseases that cause it, such as Alzheimer’s.

The Neuroimmune Interactions theme brings together UK DRI researchers investigating the relationship between the immune system and the pathological processes that underlie neurodegeneration. We aim to gain greater understanding into how immune system operates, and the cellular mechanisms that impact the health of the brain and rest of the central nervous system during ageing and in neurodegenerative diseases.

Examples of our areas of focus include understanding the following:

- How immune cells such as microglia can go awry and contribute to memory loss

- How immune and nervous cells talk to each other to ensure proper brain health

- How we can boost the immune system to clear toxic proteins
Synapse

Scientific theme co-leads: Dr Samuel Barnes (UK DRI at Imperial) & Prof Seth Grant (Univ. of Edinburgh)
Research theme project manager: Dr Sarmi Sri (UK DRI Central Team)

Weakening and loss of normal synaptic function in specific brain regions over time is a key feature of the development and progression of neurodegenerative diseases, and synapse damage and loss precede neuronal loss resulting in cognitive and motor impairments. Despite the major advances in our understanding of the molecular biology of synapses, there is still much to learn about the cause and consequences of synapse damage in neurodegenerative disorders.

The Synapse theme brings together collective expertise of UK DRI researchers to address major questions surrounding mechanisms of synapse damage from the molecular through to circuit/network levels.

Among our main questions to unlock new therapeutic and diagnostic opportunities are:

- why are some synapses vulnerable to neurodegenerative disorders whereas others are resilient?

- How do microglia target specific synapse subtypes and why this is more pronounced in advanced age?

- How do toxic protein accumulation, excitotoxicity and metabolic dyshomeostasis (secondary to hypoxia and vascular damage) contribute to synapse damage?

Read more about the synapse symposium run by UK DRI at King's in 2019
Vascular

Scientific theme lead: Prof Joanna Wardlaw (UK DRI at Edinburgh) and Dr Axel Montagne (UK DRI at Edinburgh)
Research theme project manager: Dr Sarmi Sri (UK DRI Central Team)

Vascular dementia is the second most common cause of dementia. In addition, growing epidemiology, genetic, and neuropathological evidence supports vascular dysfunction as a primary or contributory driver of disease in around 50% of all dementias. Crucially, it appears that vascular dysfunction occurs early in the course of cognitive decline, potentially in advance of neurodegenerative changes, highlighting the vascular component as an attractive and accessible target for intervention.

The Vascular theme aims to bring together both clinical and preclinical expertise from across the UK DRI and beyond to explore these opportunities further.

Among our main areas of focus are:

- vascular contributions to neurodegeneration and dementia in patient cohorts

- understanding the mechanisms behind vascular and blood-brain barrier dysfunction during ageing and disease (with a strong focus on endothelial cells)

- greater understanding of the role of glial cells in vascular dysfunction
Glia

Scientific theme co-leads: Dr Blanca Diaz-Castro (UK DRI at Edinburgh) & Prof Anna Williams (University of Edinburgh)
Research theme project manager: Dr Ruby Wallis (UK DRI Central Team)

Glia (including microglia, astrocytes, oligodendrocytes, and ependymal cells) are increasingly implicated in the development and progression of dementia. The Glia theme brings together researchers from across the UK DRI investigating the role of these cells in neurodegenerative diseases. The theme meets to share knowledge, discuss the latest developments in the field, and to identify and address key questions in glia biology.

Through regular meetings, we aim to facilitate discussions to help identify and remove critical roadblocks for understanding how glia are involved in neurodegeneration and their potential as targets for novel therapeutic interventions.
Parkinson's disease

Scientific theme co-leads: Dr Tim Bartels (UK DRI at UCL) & Dr Dayne Beccano-Kelly (UK DRI at Cardiff)
Research theme project manager: Dr Ruby Wallis (UK DRI Central Team)

Through data-driven focused meetings, the 'Parkinson's disease' Theme aims to facilitate discussions and debates that will help identify and remove critical roadblocks for understanding, diagnosing and treating Parkinson’s Disease and related synucleinopathies. As a group of leading researchers in Parkinson's disease, we will explore some of the following topics:

- Specific vulnerability of cell types
- Protein structure and folding
- Protein homeostasis (proteasome / lysosome)
- Mechanisms of spread and the gut-brain-axis
- Biomarkers
- Neuronal circuits
- Model systems
Motor neuron disease

Scientific theme co-leads: Dr Marc-David Ruepp (UK DRI at King’s), Dr Sarah Mizielinska (UK DRI at King’s) & Prof Suvankar Pal (University of Edinburgh)
Research theme project manager: Dr Ruby Wallis (UK DRI Central Team)

Amyotrophic lateral sclerosis (ALS), the most common form of MND, is a devastating neurodegenerative disease with no cure. Most cases arise sporadically with uncertain aetiology pointing to a contribution from environmental factors and polygenic risk. 10-15% of individuals have autosomal dominant disease with C9orf72 expansions and mutations in SOD1 accounting for the majority of genetic cases. >95% of all cases converge on a common pathology characterised by nuclear clearance and cytoplasmic accumulation of the RNA-binding protein TDP-43 protein.

The MND theme aims to uncover the pathways leading to motor neuron degeneration and exploit reverse translational approaches to identify new biomarkers and translatable therapeutic targets. By leveraging expertise spanning genetics, RNA biology, proteostasis, deeply clinical phenotyped registries, bioresourcing, and clinical trials, the theme integrates patient-derived insights with innovative disease models. The members aim to build a streamlined research pipeline conducive for translation of mechanistic understanding into evidence-based clinical trials, and where clinical trial data can dynamically inform discovery science. Knowledge gained from MND may illuminate related TDP-43 proteinopathies like frontotemporal dementia and Alzheimer’s disease.

Key priorities include:
- Elucidating disease heterogeneity
- Understanding RNA homeostasis dysregulation
- Generating robust TDP-43 pathology models
- Biomarker discovery