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, Erwan Bezard
Nat Commun. 2020-07-10; 11(1):
DOI: 10.1038/s41467-020-17328-9

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1. Nat Commun. 2020 Jul 10;11(1):3440. doi: 10.1038/s41467-020-17328-9.

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

Soria FN(1)(2)(3), Paviolo C(4)(5), Doudnikoff E(1)(2), Arotcarena ML(1)(2), Lee
A(4)(5), Danné N(4)(5), Mandal AK(4)(5), Gosset P(1)(2), Dehay B(1)(2), Groc
L(6)(7), Cognet L(8)(9), Bezard E(10)(11).

Author information:
(1)Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293,
33076, Bordeaux, France.
(2)Centre National de la Recherche Scientifique, IMN, UMR 5293, 33076, Bordeaux,
France.
(3)Achucarro Basque Center for Neuroscience, Universidad del País Vasco
(UPV/EHU), 48940, Leioa, Spain.
(4)Université de Bordeaux, Laboratoire Photonique Numérique et Nanosciences, UMR
5298, 33400, Talence, France.
(5)Institut d’Optique & Centre National de la Recherche Scientifique, LP2N, UMR
5298, 33400, Talence, France.
(6)Université de Bordeaux, Interdisciplinary Institute for Neuroscience, UMR
5297, 33076, Bordeaux, France.
(7)Centre National de la Recherche Scientifique, IINS, UMR 5297, 33076, Bordeaux,
France.
(8)Université de Bordeaux, Laboratoire Photonique Numérique et Nanosciences, UMR
5298, 33400, Talence, France. .
(9)Institut d’Optique & Centre National de la Recherche Scientifique, LP2N, UMR
5298, 33400, Talence, France. .
(10)Université de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293,
33076, Bordeaux, France. .
(11)Centre National de la Recherche Scientifique, IMN, UMR 5293, 33076, Bordeaux,
France. .

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.

DOI: 10.1038/s41467-020-17328-9
PMCID: PMC7351768
PMID: 32651387


Auteurs Bordeaux Neurocampus