In vitro α-synuclein neurotoxicity and spreading among neurons and astrocytes using Lewy body extracts from Parkinson disease brains.
Neurobiology of Disease. 2017-07-01; 103: 101-112
DOI: 10.1016/j.nbd.2017.04.011
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1. Neurobiol Dis. 2017 Jul;103:101-112. doi: 10.1016/j.nbd.2017.04.011. Epub 2017
Apr 11.
In vitro α-synuclein neurotoxicity and spreading among neurons and astrocytes
using Lewy body extracts from Parkinson disease brains.
Cavaliere F(1), Cerf L(2), Dehay B(3), Ramos-Gonzalez P(1), De Giorgi F(4),
Bourdenx M(3), Bessede A(2), Obeso JA(5), Matute C(1), Ichas F(4), Bezard E(6).
Author information:
(1)Departamento de Neurociencias, Achucarro Basque Center for Neuroscience,
Universidad del País Vasco (UPV/EHU) and Centro de Investigación Biomédica en Red
en Enfermedades Neurodegenerativas (CIBERNED), S-48940 Leioa, Spain.
(2)ImmuSmol, F-33600 Pessac, France.
(3)Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000
Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293,
F-33000 Bordeaux, France.
(4)Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000
Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293,
F-33000 Bordeaux, France; INSERM U1084 Laboratoire de Neurosciences
Experimentales et Cliniques, F-86000 Poitiers, France.
(5)HM Centro Integral de Neurociencias A.C. (CINAC), HM Puerta del Sur and
CIBERNED and CEU-San Pablo University Madrid, E-28938 Mostoles, Spain.
(6)Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000
Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293,
F-33000 Bordeaux, France; Motac Neuroscience, UK-M15 6WE Manchester, UK.
Electronic address: .
Synucleinopathies are a group of diseases characterized by the presence of
intracellular protein aggregates containing α-synuclein (α-syn). While α-syn
aggregates have been shown to induce multimodal cellular dysfunctions, uptake and
transport mechanisms remain unclear. Using high-content imaging on cortical
neurons and astrocytes, we here define the kinetics of neuronal and astrocytic
abnormalities induced by human-derived α-syn aggregates grounding the use of such
system to identify and test putative therapeutic compounds. We then aimed at
characterizing uptake and transport mechanisms using primary cultures of cortical
neurons and astrocytes either in single well or in microfluidic chambers allowing
connection between cells and cell-types. We report that astrocytes take up
α-syn-aggregates far more efficiently than neurons through an endocytic event. We
also highlight that active α-syn transport occurs between cells and any
cell-types. Of special interest regarding the disease, we also show that uptake
and spreading of α-syn from astrocytes to neurons can lead to neuronal death.
Altogether, we here show that patients-derived α-synuclein aggregates, which are
taken up by neurons and astrocytes, induce a differential endogenous response in
the two cell types including a peculiar astrocytic toxic gain-of-function that
leads to neuronal death.
Copyright © 2017 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.nbd.2017.04.011
PMID: 28411117 [Indexed for MEDLINE]