This is one of a series of posts discussing our 2019 crop of Lister Fellows. Each of the new Fellows were officially awarded their prestigious Lister Institute research prize at our Annual Event at the University of Oxford in November 2019. In this post we meet Dr William McEwan of the University of Cambridge.
Dr McEwan studies ordered assemblies of proteins and their relationships with neurodegenerative disease. His work is motivated by the potential that preventing protein assembly could provide a route to new therapies.
The aggregation of proteins into long, ordered fibres is implicated in a variety of neurodegenerative diseases, operating in a complex intracellular environment that requires a range of techniques and approaches to fully understand and characterise.
Dr McEwan is researching the role of protein assembly in neurodegeneration in order to study how our cells can defend against it.Neurodegenerative disease primarily refers to any disorder that affects the neurons in the brain, such as Alzheimer’s, Huntington’s or Parkinson’s diseases. They are highly serious and are increasingly prevalent disorders that affect people all around the world.
The brains of patients of these diseases contain assemblies of particular proteins, such as tau in Alzheimer’s disease and alpha-synuclein in Parkinson’s disease. These assemblies are now thought to play a significant role in the spread of neurodegeneration within the brain. They can gain access to naïve cells and promote templated aggregation that results in their replication similar to the behaviour of pathogens in classical infection.
This insight is enabling Dr McEwan’s team to study protein aggregation as a host-pathogen relationship; gaining a deeper understanding of the mechanisms of protein assembly itself and the ability of the host to exert a level of control over the aggregation process.
Dr McEwan’s group is currently determining the ability of an observed mechanism, in which host cells can be ‘educated’ to detect protein assemblies as a threat, to confer protection in a range of culture-based and animal models of neurodegeneration.
The group has identified that cells containing assemblies of tau (a protein that aggregates in around 20 different neurodegenerative diseases besides Alzheimer’s) can have antibodies trafficked into them under the right conditions.
Once inside, the antibodies can stimulate the host cells to specifically degrade the tau assembly. This is an immune mechanism that previously was thought to be specific to classical pathogens such as viruses. The work therefore demonstrates that the intracellular immune system can be repurposed to defend against protein assemblies.
The team is currently determining the applicability of this method to confer such protection in vivo. The ultimate aim of the work is to develop universal systems to elicit specific intracellular protein degradation.
Dr. McEwan’s laboratory is situated in the UK Dementia Research Institute (DRI) at the University of Cambridge, UK and lies within the Department of Clinical Neurosciences. You can find out more about his lab and work on the UK DRI website or on his personal website.
We are very pleased to be supporting Dr McEwan’s research through a Lister Research Prize and are looking forward to hearing more about his progress in the future.
