Redesigning technology to monitor sleep disruption in mouse models of disease
Dr Mathieu Nollet and Dr Berta Anuncibay Soto, UK DRI at Imperial
We know that changes in sleep-wake cycle happen early in the course of many diseases that cause dementia. It is crucial to be able to use animal models of disease to understand how and why this happens. But how can you monitor sleep, body temperature, movement and other measures in a mouse when most available technology is bulky and affects behaviour? Dr Nollet and Dr Anuncibay will join forces to redesign this technology, making it less invasive while monitoring mice.
With these tools they will study how changes in sleep patterns impact the development of disease processes in dementia and influence the production of stress hormones. Their improved method of studying mice will not only be of benefit to the wider research community but will help us understand the underlying causes of the diseases that cause dementia.
Project title: ‘Developing assays linking sleep disruption and circadian changes in locomotor activity, body temperature and stress response in mouse models of dementia’
Harnessing DNA repair to treat Huntington’s disease
Dr Meghan Larin, UK DRI Cardiff
Huntington’s disease is caused by an expansion of the CAG repeat sequence in the HTT gene, which causes a defect in the resulting protein huntingtin. These repeat expansions are particularly important as they have been shown to play a role in the age of onset and disease severity of Huntington’s. Determining new ways to shorten these repeat lengths may help in the development of new treatments for Huntington’s.
Dr Larin is investigating whether these expansions can be prevented by determining the proteins associated with expanded CAG repeats. She suspects that proteins involved in repairing DNA may provide the answer, as some have been shown to be involved CAG repeat expansions in Huntington’s disease. Dr Larin will use a new technique developed in her research group to explore this idea further, which may aid in the identification of new protein associations and open up new avenues for treatment.
Project title: ‘Exploring the proteome of CAG/CTG repeat expansions’
Could hibernation hold the key to repairing the brain in dementia?
Dr Heather Smith, UK DRI at Cambridge
Neurons communicate with each other using several tiny connections called synapses and loss of these structures is an early feature of diseases that cause dementia. Saving synapses could therefore offer a powerful therapeutic tool. Dr Smith’s research looks at the mechanisms which repair synapses, particularly those that occur during hibernation, which have been shown to fail early in mouse models of the disease. She will use a range of complementary techniques to study how these repair mechanisms work and whether this knowledge can be used to develop targets for human diseases that cause dementia.
Project title: ‘Investigating the molecular mechanism underlying synapse regeneration and its failure in ageing and disease’
Using small antibodies to remove harmful tau protein in diseases that cause dementia
Dr Edoardo Moretto, UK DRI at UCL
Collaborator: Jobert Vargas, PhD student, MNP lab, UCL IoN Dept of Neuromuscular diseases
Dr Moretto’s research focuses on tau, a key protein that forms harmful aggregates or clumps within neurons in diseases such as Alzheimer’s and Frontotemporal dementia. He is developing a strategy to eliminate this abnormal tau as a potential therapeutic option for these pathologies. To do this, he is investigating if autophagy, a process that helps clear cellular waste, could be directed to tau using small antibodies delivered via gene therapy. If successful, this approach could remove harmful tau protein and pave the way for novel highly-specific gene therapies for dementia.
Project title: ‘Autophagy-driven clearance of pathological tau via single-chain variable fragment antibody’
Using state-of-the-art cryo-electron microscopy to investigate the stress protein PERK and its interactions in disease
Dr Adrian Butcher, UK DRI at Cambridge
The protein PERK has been shown to be involved in toxic signalling across the board in diseases that cause dementia. Dr Butcher will use state-of-the-art cryo-electron microscopy to increase our understanding of the structure of PERK and the proteins that it interacts with that drive this signalling in these disorders. Filling this knowledge gap will help us understand PERK’s role in the toxic effects observed in disease, potentially opening up new avenues for treatments.
Project title: Defining the structural basis for non-canonical protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) over-activation in neurodegenerative disease.
Article published: 04 May 2020