"We aim to harness the immune system and target protein aggregation in neurodegenerative disease." Will McEwan
Sir Henry Dale Fellow and UK DRI Group Leader

A Sir Henry Dale Fellow, Prof Will McEwan joined the UK DRI in 2017 following his postdoctoral training at the MRC Laboratory of Molecular Biology in Cambridge. Will trained as a viral immunologist and during his postdoc co-discovered and characterised the novel antibody receptor TRIM21. At the UK DRI at Cambridge, he will utilise his expertise in viral infection and apply it in the context of protein misfolding in neurodegenerative disease.

1. At a glance

Stopping the spread of toxic proteins in the brain

Many neurodegenerative conditions, including Alzheimer’s disease, are characterised by the formation of abnormal protein structures in the brain. Within healthy neurons, a protein called tau binds to and stabilises the cell’s scaffolding and transport networks. But things can go wrong in disease – the tau molecules start to behave abnormally, detaching from these networks, clumping together and forming toxic aggregates or 'clumps'.

Scientists know that a build-up of the abnormal tau protein plays a critical role in the development of several neurodegenerative diseases, but the exact mechanisms involved remain unclear. Until recently, they thought that the abnormal tau molecules were only generated from within neuron. However, recent evidence suggests toxic tau protein spreads from neuron to neuron across the brain, corrupting previously healthy tau protein molecules and propagating neuronal death.

Prof Will McEwan is aiming to understand the biological mechanisms behind the spreading of tau aggregates through the brain. He hopes to identify avenues for potential new treatments that can interfere with these processes and slow down or stop disease progression. In particular, he is exploring the potential of manipulating a molecule called TRIM21 as a way of destroying the toxic proteins, preventing the spread of toxic tau aggregates and their resulting damage to the brain.

2. Scientific goals

Several neurodegenerative diseases are characterised by the deposition of ordered, filamentous assemblies that consist predominantly of a single type of protein. Filaments of tau are found in the brains of people living with Alzheimer’s disease (AD), as well as twenty other less common neurological diseases. This aggregation was long considered to be a cell-autonomous feature of disease progression. However, several recent lines of evidence support the notion that aggregation can spread within affected brains through a templated aggregation process whereby fibrillar assemblies convert native proteins to the assembled, pathological form. For instance, the introduction of tau assemblies to the brains of mice induces the aggregation of human transgenic or endogenously expressed tau. While these findings have been replicated in cell-based models, there is very little understanding of what cellular processes can influence seeded protein aggregation. This limits our ability to develop therapeutic strategies that could act to prevent the spread of misfolded proteins in the brain.

Prof Will McEwan and his team have demonstrated that an antiviral cytoplasmic antibody receptor called TRIM21 can be repurposed to elicit the degradation of specific intracellular proteins. This enables depletion of target proteins over a very rapid time-course, leading in many cases to the reduction of protein levels to below detectable thresholds within hours.

Importantly, they have also shown that TRIM21 and intracellular antibodies may have therapeutic relevance to neurodegenerative diseases. Assemblies of tau can import antibodies to the cell and are subsequently detected and inactivated by TRIM21. This acts to prevent further spreading of misfolded tau. In this way, they have demonstrated that immune pathways can be redirected to prevent seeded protein aggregation, suggesting a new route towards therapeutics.

Main objectives and research goals:

1. Understand the cellular role in the uptake, cellular entry and seeded aggregation of tau

2. Investigate the innate immune mechanisms that can destroy protein aggregates

3. Exploit small molecule and biologic strategies to intercept protein aggregation

3. Team members

Dr Kelsey Hanson (Postdoctoral Researcher)
Dr Aamir Mukadam (Postdoctoral Researcher)
Sophie Keeling (Research Assistant)
Annabel Smith (Research Assistant)
Anna Brown (Research Assistant)
Matthew Reid (Research Assistant)
Melissa Huang (PhD Student)
Sophie Sanford (PhD student)
Jonathan Benn (PhD student)
Julia Zbeigly (PhD student)
Kimberly Cheam (PhD student)

4. Collaborations

Within UK DRI:

Prof David Klenerman, UK DRI at Cambridge

Beyond UK DRI:

5. Topics

Intracellular antibodies, TRIM21, tau seeding, protein aggregation, Alzheimer’s disease

6. Techniques

CRISPR screening, animal and cell-based models of disease

7. Key publications

Cholesterol determines the cytosolic entry and seeded aggregation of tau. Tuck BJ, Miller LVC, Katsinelos T, Smith AE, Wilson EL, Keeling S, Cheng S, Vaysburd MJ, Knox C, Tredgett L, Metzakopian E, James LC, McEwan WA Cell Rep. 2022 May 3;39(5):110776. doi: 10.1016/j.celrep.2022.110776.

Tau assemblies do not behave like independently acting prion-like particles in mouse neural tissue. Miller LVC, Mukadam AS, Durrant CS, Vaysburd MJ, Katsinelos T, Tuck BJ, Sanford S, Sheppard O, Knox C, Cheng S, James LC, Coleman MP, McEwan WA. Acta Neuropathol Commun. 2021 Mar 12;9(1):41. doi: 10.1186/s40478-021-01141-6.

Target-induced clustering activates Trim-Away of pathogens and proteins Zeng J, Santos AF, Mukadam AS, Osswald M, Jacques DA, Dickson CF, McLaughlin SH, Johnson CM, Kiss L, Luptak J, Renner N, Vaysburd M, McEwan WA, Morais-de-Sá E, Clift D, James LC. Nat Struct Mol Biol. 2021 Feb 25. doi: 10.1038/s41594-021-00560-2.

Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation. McEwan WA, Falcon B, Vaysburd M, Clift D, Oblak AL, Ghetti B, Goedert M, James LC. Proc Natl Acad Sci U S A. 2017 Jan 114 574-579

Will McEwan