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 amyloid filaments in the central nervous system. This includes the protein TDP-43 in motor neuron diseases (including amyotrophic lateral sclerosis) and multiple dementias. In addition, our group recently discovered that TDP-43 co-assembles with a second protein, annexin A11, in several subtypes of these diseases, and that the assembly of a third protein, TAF15, characterises remaining disease subtypes.
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 a lack of model systems that accurately recapitulate assembly and, consequently, 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 protein filaments in vitro. Our group has previously determined the structures of TDP-43, annexin A11 and TAF15 filaments from patient brains using electron cryomicroscopy (cryo-EM). This has revealed that these proteins form distinct filament structures in different diseases. This project will use protein biochemistry and cryo-EM. In vitro models will enable investigation of the structural mechanisms of assembly, as well as screens for novel clinical tools that target assembly.
The second project aims to reproduce the structures of pathological protein filaments in cell and tissue cultures. This builds on our group’s work on establishing neuronal and glial cell culture systems to investigate pathological TDP-43 assembly. We will use electron cryotomography (cryo-ET) to visualise the cellular environments and interactions of the filaments at molecular resolution. This builds on our group’s previous work on establishing the use of cryo-ET to visualise the molecular interactions of filaments in patient brain environments. An understanding of the molecular environments and interactions of filaments will shed light on the cellular mechanisms of assembly.