diseases (PMID 39260416), and that the assembly of a third protein, TAF15, characterises remaining disease subtypes (PMIDs 38057661 and 41648099).
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 cryo-microscopy (cryo-EM) (PMIDs 34880495, 37532939, 38057661, 39260416 and 41648099). 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 (PMID 41659424). We will use electron cryo-tomography (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 enivronments (PMIDs 37163117 and 41659424). An understanding of the molecular environments and interactions of filaments will shed light on the cellular mechanisms of assembly.
Funding Notes
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References
Chen R, Stockwell I, Pierce JC, Peak-Chew SY, Huang M, Newell K, Ghetti B, Cousin MA, Greger IH, Ryskeldi-Falcon B (2026). Pathological TDP-43 filaments accumulate at synapses and cause synaptic dysfunction. BioRxiv DOI: 10.64898/2026.01.27.701787.
Tetter S, Varghese NR, Murzin AG, De Coster W, Van den Broeck M, Roeber S, Joseph JT, Newell K, Castellani R, Das S, Ang LC, Synofzik M, Herms J, Rademakers R, Ghetti B, Lashley T, Mackenzie IRA, Neumann M, Ryskeldi-Falcon B (2026). Distinct TAF15 amyloid filament folds define multiple subtypes of FTLD-TAF15. BioRxiv DOI: 10.64898/2026.01.12.698957.
Fowler SL, Behr TS, Turkes E, Maglio Cauhy P, Foiani MS, Schaler A, Crowley G, Bez S, Ficulle E, Tsefou E, O'Brien DP, Fischer R, Geary B, Gaur P, Miller C, D'Acunzo P, Levy E, Duff KE, Ryskeldi-Falcon B (2025). Tau filaments are tethered within brain extracellular vesicles in Alzheimer's disease. Nature Neuroscience 28, 40-48.
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 (2024). Heteromeric amyloid filaments of ANXA11 and TDP-43 in FTLD-TDP Type C. Nature 634, 662-668.
Tetter S, Arseni D, Murzin AG, Buhidma Y, Peak-Chew SY, Garringer HJ, Newell K, Vidal R, Apostolova LG, Lashley T, Ghetti B, Ryskeldi-Falcon B (2024). TAF15 amyloid filaments in frontotemporal lobar degeneration. Nature 625, 345-35.
Scheres S, Ryskeldi-Falcon B, Goedert M (2023). Molecular pathology of neurodegenerative diseases by cryo-EM of amyloids. Nature 621, 701-710.
Arseni D, Chen R, Murzin AG, Peak-Chew SY, Garringer HJ, Newell K, Kametani F, Robinson AC, Vidal R, Ghetti B, Hasegawa M, Ryskeldi-Falcon B (2023). TDP-43 forms amyloid filaments with a distinct fold in type A FTLD-TDP. Nature 620, 898-903.
Arseni D, Hasegawa M, Murzin AG, Kametani F, Arai M, Yoshida M, Ryskeldi-Falcon B (2022). Structure of pathological TDP-43 filaments from ALS with FTLD. Nature 601, 139-143.
