Spreading protein misfolding diseases

The cytoplasmic protein tau forms filamentous aggregates that are found in neurons of Alzheimer’s disease patients as well as sufferers of other neurodegenerative diseases. The abundance of tau filaments in the brain corresponds well to the degree of neuropathology. Futhermore, mutations in tau can lead to familial dementias that are characterised by the presence of tau filaments. These lines of evidence suggest a central role of tau aggregation in disease progression. A series of critical experiments over the past decade demonstrate that tau filaments have the ability to spread between cells, corrupting native tau into the aggregated form. Thus filamentous tau may spread through the brain in a similar manner to viral infection, i.e. by transferring between cells and consuming host resources. Ongoing projects aim to uncover the molecular basis of tau replication in reconstituted in vitro systems and cell-based models.

Adenovirus particles. Antibody neutralization of adenovirus infection is dependent on the dedicated cytosolic antibody TRIM21. Negative stain electron micrograph (W. McEwan)

Intracellular innate immunity

Over the past two decades, the cytosol has been shown to harbour numerous sensors capable of recognising and destroying virus particles. Included among these is the newly identified cytoplasmic receptor for antibody, TRIM21. Viruses can import antibodies that are attached to their surfaces to the cytoplasm during infection. Upon binding these intracellular antibodies, TRIM21 mounts a potent degradation response, leading to the destruction of the virus-antibody complex and an infection-free state. Experiments have demonstrated that any antibody-bound particle present in the cytoplasm will become a target for TRIM21. We are therefore asking whether spreading misfolded proteins may be targeted in this manner. In support of this possibility, in 2017 we showed that assemblies of tau can be inactivated by TRIM21 in cell-based models of seeded tau aggregation (McEwan et al. 2017). Ongoing work is uncovering the molecular machinery that enables the cytosolic inactivation of tau seeds.

Antibody therapy against tau

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.