Research

The abnormal filamentous assembly of specific proteins within neurons and glia is a hallmark of neurodegenerative diseases. These proteins include TAR DNA-binding protein 43 (TDP-43), tau, α-synuclein and TATA-box binding protein associated factor 15 (TAF15). They form amyloid filament structures enriched in intermolecular β-sheets. Mutations in the genes encoding these proteins lead to assembly and inherited neurodegenerative disease, demonstrating a causal role. Assemblies arise in discrete brain regions, from where they appear to propagate (spread and amplify) within connected brain networks, ultimately leading to neurodegeneration.

The background shows assembled tau inclusions within neurons and astrocytes (purple) in the neurodegenerative disease chronic traumatic encephalopathy (CTE). The foreground shows the major component of these inclusions, the CTE Type I tau filament, formed from two protofilaments (light and dark pink) centered around non-proteinaceous molecules (red).

We work to understand the molecular basis of protein assembly into amyloid filaments in neurodegenerative disease. Key questions that interest us are: How do assemblies form and propagate? How does this contribute to nerve cell degeneration? Why are only some cell populations in the brain vulnerable? Why does selective vulnerability differ between diseases?

Hypothesised stages in the transneuronal propagation of protein assemblies (blue) in neurodegenerative disease.

To answer these questions, we combine structural and cell biology, using high-resolution electron cryo-microscopy (cryo-EM) with patient samples and advanced models of assembly in neuronal and glial cells. Cryo-EM of assembly structures from human brains has revealed the existence of amyloid filaments with disease-specific folds and non-proteinaceous components. We are now studying how these structures relate to selective cell vulnerability by focusing on the molecular interactions between assemblies and brain cells.