Protein aggregation 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.
Selected publications
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).
Neurotransmitter receptors at the single-molecule level and their interactions with protein aggregates
The classical quasi-static view of the synapse has drastically changed over the past years, giving way to a model in which the dynamic behaviour of synaptic components modulates transmission and plasticity. This change of paradigm is largely due to the development of single-molecule imaging techniques that allow tracking receptors with high spatial and temporal resolution in living neurons. The body of work regarding diffusion of receptors in the plasma membrane has been done almost entirely in cultured neurons, a system which is useful but greatly differs from neurons in intact brain preparations. In our lab, we are interested in developing tools to study these dynamic properties of neurotransmitter receptors and ion channels in the brain in vivo. We are now able to use diffusion measurements as reporters of interactions between single receptors and protein aggregates.
Selected publications
Varela J, Dupuis J, Etchepare L, Espana A, Cognet L and Groc L. “Targeting neurotransmitter receptors with nanoparticles in vivo allows single molecule tracking in brain tissue”. Nature Communications, 7:10947 (2016).
Varela J*, Ferreira J*, Dupuis JP*, Durand P, Bouchet D, and Groc L. “Single nanoparticle tracking of NMDA receptors in cultured and intact brain tissue”. Neurophotonics, 3:41808 (2016).
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 suitable for this task. Our knowledge about the organisation of the extracellular space of the brain is surprisingly poor, mainly based on electron microscopy images which lack important aspects of native brain tissue as the technique is not compatible with living samples.
Protein aggregates and metabolites circulate the ECS and are cleared to the blood and cerebrospinal fluid (CSF). The main routes are thought to be the transport through the blood-brain barrier and the recently discovered glymphatic pathway, a paravascular flow of the interstitial fluid (ISF) highly regulated by astrocytes. This clearance mechanism mainly functions during sleep, which is consistent with the ECS volume increase. This novel mechanism based on bulk flow of CSF is still controversial, and to understand this process in depth we need to be able to image the transport of aggregates along the ECS in vivo.
Selected publications
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 (Univ. of Cambridge)
Prof. Peter St. George-Hyslop (Univ. of Cambridge and Univ. of Toronto)
Prof. Steven F. Lee (Univ. of Cambridge)
Dr. Laurent Groc (CNRS, Univ. of Bordeaux)
Dr. Laurent Cognet (CNRS, Univ. of Bordeaux)