Synucleinopathy alters nanoscale organization and diffusion in the brain extracellular space through hyaluronan remodeling

Federico N. Soria, Chiara Paviolo, Evelyne Doudnikoff, Marie-Laure Arotcarena, Antony Lee, Noémie Danné, Amit Kumar Mandal, Philippe Gosset, Benjamin Dehay, Laurent Groc, Laurent Cognet () and Erwan Bezard ()
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Federico N. Soria: Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293
Chiara Paviolo: Université de Bordeaux, Laboratoire Photonique Numérique et Nanosciences, UMR 5298
Evelyne Doudnikoff: Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293
Marie-Laure Arotcarena: Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293
Antony Lee: Université de Bordeaux, Laboratoire Photonique Numérique et Nanosciences, UMR 5298
Noémie Danné: Université de Bordeaux, Laboratoire Photonique Numérique et Nanosciences, UMR 5298
Amit Kumar Mandal: Université de Bordeaux, Laboratoire Photonique Numérique et Nanosciences, UMR 5298
Philippe Gosset: Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293
Benjamin Dehay: Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293
Laurent Groc: Université de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297
Laurent Cognet: Université de Bordeaux, Laboratoire Photonique Numérique et Nanosciences, UMR 5298
Erwan Bezard: Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract In recent years, exploration of the brain extracellular space (ECS) has made remarkable progress, including nanoscopic characterizations. However, whether ECS precise conformation is altered during brain pathology remains unknown. Here we study the nanoscale organization of pathological ECS in adult mice under degenerative conditions. Using electron microscopy in cryofixed tissue and single nanotube tracking in live brain slices combined with super-resolution imaging analysis, we find enlarged ECS dimensions and increased nanoscale diffusion after α-synuclein-induced neurodegeneration. These animals display a degraded hyaluronan matrix in areas close to reactive microglia. Furthermore, experimental hyaluronan depletion in vivo reduces dopaminergic cell loss and α-synuclein load, induces microgliosis and increases ECS diffusivity, highlighting hyaluronan as diffusional barrier and local tissue organizer. These findings demonstrate the interplay of ECS, extracellular matrix and glia in pathology, unraveling ECS features relevant for the α-synuclein propagation hypothesis and suggesting matrix manipulation as a disease-modifying strategy.

Date: 2020
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DOI: 10.1038/s41467-020-17328-9

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