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 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 (PMID 39260416), and that the assembly of a third protein, TAF15, characterises remaining disease subtypes (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 and 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 cryo-microscopy (cryo-EM) (PMIDs 34880495, 37532939, 38057661 and 39260416). This has revealed that these proteins form distinct filament structures in different 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 reproduce the structures of pathological protein filaments in cell and tissue cultures. This builds on our group's work in establishing neuronal and glial cell culture systems to investigate pathological TDP-43 assembly. We will use electron cryo-tomography (cryo-ET) to visualise the cellular environments and interactions of the filaments. 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.

References

Tau filaments are tethered within brain extracellular vesicles in Alzheimer’s disease
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Nature Neuroscience 28(1): 40-48 (2025)

Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP type C
Arseni D, Nonaka T, Jacobsen MH, Murzin AG, Cracco L, Peak-Chew SY, Garringer HJ, Kawakami I, Suzuki H, Onaya M, Saito Y, Murayama S, Geula C, Vidal R, Newell KL, Mesulam M, Ghetti B, Hasegawa M, Ryskeldi-Falcon B
Nature 634(8034): 662-668 (2024)

Molecular pathology of neurodegenerative diseases by cryo-EM of amyloids
Scheres SHW, Ryskeldi-Falcon B, Goedert M
Nature 621(7980): 701-710 (2023)

TDP-43 forms amyloid filaments with a distinct fold in type A FTLD-TDP
Arseni D, Chen R, Murzin AG, Peak-Chew SY, Garringer HJ, Newell KL, Kametani F, Robinson AC, Vidal R, Ghetti B, Hasegawa M, Ryskeldi-Falcon B
Nature 620(7975): 898-903 (2023)

Structure of pathological TDP-43 filaments from ALS with FTLD
Arseni D, Hasegawa M, Murzin AG, Kametani F, Arai M, Yoshida M, Ryskeldi-Falcon B
Nature 601(7891): 139-143 (2022)