1) How do antibodies protect against tau pathology?
There is a concerted effort to develop antibody therapies against tau for the treatment of Alzheimer’s disease and other diseases where tau pathology is present. Therapies are currently entering Phase I trials and are considered one of the most promising therapeutic approaches within sight. However, the mechanism by which antibodies provide their protective effect in this context is poorly understood. A main goal of the lab is to determine how antibodies protect against tau pathology with the aim of informing how future therapies may be better designed to exploit protective mechanisms. We recently showed that TRIM21 can neutralize tau seeding in a manner analogous to neutralization of viruses (McEwan et al. 2017 PNAS). We are investigating the relevance of intracellular neutralization in models of tau pathology.
2) How are aggregated proteins resolved by cellular machinery?
The activity of TRIM21 appears to promote a particularly potent degradation response, capable of destroying compact and β-rich structures including virus particles and tau fibrils. This requires the ubiquitin ligase activity of its N-terminal RING domain and the sequential addition of ubiquitin chains via the E2 ligases Ube2N and Ube2W. However, beyond this, the host machinery required for this potent degradation response is not clear. There is evidence that TRIM21 requires the ubiquitin-selective protein unfoldase p97/VCP for pre-processing substrates before proteasomal degradation. Our current work is illuminating the mechanisms of TRIM21 degradation with particular reference to tau fibrils. This will provide insight into the cellular mechanisms that enable the cytoplasmic destruction of protein complexes.
3) Genetic control of seeded protein aggregation
The conversion of proteins to an assembled state is a common driver or several neurodegenerative diseases. However, the mechanisms by which cells may control this process are largely unknown. We are contributing to the IMRPiND collaboration, a Europe-wide consortium dedicated to understanding seeded protein aggregation. As part of this work, we are contributing to CRISPR knockout screens that seek to identify proteins critical to seeded tau aggregation. This will provide a new understanding of the cellular mechanisms that govern protein aggregation and identify new targets for therapeutic intervention in neurodegeneration.
4) Drug discovery
In collaboration with the Drug Discovery Unit at the University of Dundee, and Takeda, we are identifying compounds with the ability to prevent seeded tau aggregation. For this we are making use of cell-based seeding assays that monitor the aggregation of fluorescent full-length tau isoforms (McEwan et al. 2017 PNAS). The screen provides an opportunity to discover new cellular mechanisms involved in seeding and has identified hit compounds that are currently being explored as potential therapeutics.