Structural features of protein aggregates in neurodegeneration

We are interested in the mechanisms that drive neurodegeneration, and more specifically, how soluble proteins aggregate and form amyloids that are toxic to cells. We develop optical methods to infer properties of protein aggregates and can help us to better understand the underlying causes of diseases such as Alzheimer or Parkinson. We are also interested in phase separation of proteins and how these transitions are related to diseases such as amyotrophic lateral sclerosis or of frontotemporal lobar dementia.

Varela J, Rodrigues M, De S, Flagemeier P, Dobson CM, Klenerman D, Lee SF. “Optical structural analysis of individual α-synuclein oligomers”. Angewandte Chemie International Edition, 4886–4890 (2018)

Qamar S*, Wang G*, Randle S*, Ruggeri F*, Varela J*, Lin J*, Phillips E*, Miyashita A, Williams G, Strohl F, Meadows W, Ferry R, Dardov V, Tartaglia G, Farrer L, Kaminski Schierle G, Kaminski C, Holt C, Fraser P, Schmitt-Ulms G, Klenerman D, Knowles T, Vendruscolo M, St George-Hyslop P. “FUS Phase Separation Is Modulated by a Molecular Chaperone and Methylation of Arginine Cation-π Interactions”. Cell, 720–734 (2018).

 

Toxicity of protein aggregates in neurodegeneration

We use complex brain models combined with advanced microscopy approaches — including single-molecule imaging, calcium imaging and optogenetics — to dissect the cellular toxicity pathways triggered by disease-associated protein aggregates. A central aim of this research line is to understand how aggregates with different structural configurations engage distinct mechanisms of toxicity. We investigate how different aggregate species affect neuronal and astrocytic networks, as well as how they interact with microglia, border-associated macrophages and immune cells in the meninges.

Metodieva V, Marchese S, Esposito P, Danial JSH, Di Falco A, De S, Klenerman D, Varela JA. “Divergent toxicity mechanisms of amyloid-beta aggregates arising from a single aggregation reaction.” Cell Reports, 22;45(7):117595 (2026).

 

Clearance of protein aggregates from the extracellular space of the brain

The extracellular space of the brain occupies approximately 20% of the brain volume, but it is almost unexplored due to the lack of techniques that can resolve nanoscale geometries in vivo. Protein aggregates and metabolites circulate the extracellular space and are cleared to the blood, to the cerebrospinal fluid and to the lymphatic system. Our knowledge about the pathways that clear protein aggregates is still poor and highly controversial due to the lack of imaging tools suited for this purpose. We develop a range of imaging techniques based on nanoparticle tracking to study how the extracellular space is organised and how it is dynamically regulated by the adrenergic system. We also study how AQP4 arrays in astrocytes are tuned by adrenergic modulation, and how this affects the extracellular space architecture.

Zepernick AL, Metodieva V, Pelegrina-Hidalgo N, Lippert AH, Horrocks MH, Varela JA. “Single-molecule imaging of aquaporin-4 array dynamics in astrocytes.” Nanoscale – 16: 9576-9582 (2024).

Godin A*, Varela J*, Gao Z*, Danne N, Dupuis J, Lounis B, Groc L, Cognet L. “Single-nanotube tracking reveals the nanoscale organization of the extracellular space in the live brain”. Nature Nanotechnology, 12, 238–243 (2017).

External collaborators:

Prof. David Klenerman (University of Cambridge)

Prof. Peter St. George-Hyslop (Columbia University and University of Toronto)

Prof. Menna Clatworthy (University of Cambridge)

Prof. Mathew Horrocks (University of Edinburgh)