King's College London

Professor Jernej Ule, Van Geest Professor of Neurodegeneration Research and Centre Director of the UK DRI at King’s, will co-lead a project awarded £3.8m as part of a Wellcome Trust Discovery Award to fund research into cellular mechanisms that may protect neurons from damage due to cellular stress or ageing.

The project will build on Professor Ule’s group’s recent discovery of interstasis, a mechanism by which cells regulate proteins that like to cluster together into tiny liquid-like compartments called ‘condensates’ that help cells organise proteins and RNA molecules. Condensates need to be tightly regulated, however, to prevent their transition into toxic protein clumps.

Now, a new collaborative study between researchers at the UK Dementia Research Institute at King’s College London and University College London (UCL) will investigate how interstasis may protect against the formation of toxic clumps, and how this could protect neurons from stress and contribute to heathy brain ageing.

Professor Ule will collaborate with Dr Mathieu Bourdenx, Group Leader at the UK DRI at UCL, who will lead on screening small molecules, such as proteins and RNA, to understand how they interact with each other and mechanisms such as interstasis.

In healthy cells, proteins perform the everyday tasks that keep the cell functioning, while RNA carries the genetic instructions needed to make new proteins from DNA. In many age-related diseases, including Alzheimer's disease and motor neuron disease, specific proteins form toxic clumps inside cells, which disrupt normal cellular

Interstasis lets cells sense the accumulation of proteins in condensates and regulate how many more of these proteins are produced. To do this, the condensate-prone proteins trap their own mRNAs (which carry the instructions for making proteins), which slows down further production of these proteins.

The new grant will allow researchers to interrogate the role of interstasis in regulating neuronal condensates and whether this could help protect from the production of toxic clumps. They will investigate how this mechanism may change when neurons experience stress due to ageing or environmental factors.

“Our project aims to reveal how genes and environmental factors work together to maintain the delicate balance of condensates within cells. We will study the crosstalk between interstasis and the known protein clearance mechanisms to help explain how neurons remain healthy during ageing," commented Dr Mathieu Bourdenx, Group Leader at the UK DRI at UCL.