Pathological protein assembly in neurodegenerative diseases

Neurodegenerative diseases are one of the greatest health challenges facing our society. This large group of diseases is characterised by the pathological assembly of specific proteins into filaments in the central nervous system. This includes the protein TDP-43 in amyotrophic lateral sclerosis (motor neuron disease) and multiple dementias. In addition, our group recently discovered that the assembly of another protein, TAF15, characterises additional types of these diseases (PMID 38057661).

Human genetic studies have established a causal role for assembly in neurodegeneration. Therefore, targeting this process has immense potential for the diagnosis and treatment of neurodegenerative diseases. However, progress is currently prevented by the lack of model systems that accurately recapitulate assembly, as well as a limited understanding of the molecular mechanisms of assembly.

Two possible PhD projects are available in our group that seek to address these fundamental problems:

The first project aims to reproduce the structures of pathological TDP-43 and TAF15 filaments in vitro. Our group has previously determined the structures of TDP-43 and TAF15 filaments from patient brains using electron cryo-microscopy (cryo-EM) (PMIDs 34880495, 37532939, 38057661 and 38979278). This has revealed that these proteins form distinct filament structures in different neurodegenerative diseases. This project will use protein biochemistry and cryo-EM. Such models would enable investigation of the structural mechanisms of assembly, as well as screens for novel clinical tools that target assembly. 

The second project aims to use electron cryo-tomography (cryo-ET) to visualise the cellular environments and interactions of TDP-43 and TAF15 filaments at molecular resolution in human brain and model systems. This builds on our group’s previous work in establishing the use of cryo-ET to visualise the molecular interactions of tau filaments in extracellular vesicles from patient brain (PMID 37163117). An understanding of these molecular environments and interactions will shed light on the cellular mechanisms of assembly.