Grants awarded

Self-propagating protein conformations as targets of intracellular immunity

Grantholder:

Dr William McEwan

University of Cambridge

United Kingdom

The immune system is tasked with the detection and destruction of pathogens. Prion-like proteins, whose replication is thought to underlie neurodegenerative diseases, are the simplest type of pathogen but the hardest to protect against. This is because they are formed from self-derived material, which makes them difficult to detect, and they are highly compact structures, making them difficult to destroy. There is accordingly little understanding of how the immune system can effectively limit the spread of prion-like proteins.

I have co-discovered a novel antibody receptor, TRIM21, which can detect antibody-coated viruses inside the cell and strip them apart, preventing them from replicating. I will investigate how this mechanism could be redirected to target prion-like proteins using therapeutic antibodies. I have established experimental systems to allow the replication of tau, a prion-like protein seen in Alzheimer’s disease, to be studied in detail. These assays will be used to determine the molecular mechanisms by which protein pathogens are neutralised. In parallel, I will use mouse and stem cell-derived models of tau pathology to test whether this TRIM21-dependent mechanism can provide protection in a physiological setting.

These results could provide a mechanism-based strategy for antibody-based therapies for neurodegeneration.