[Neurobiology of Disease] In vitro α-synuclein neurotoxicity and spreading among neurons and astrocy
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.
Fabio Cavalierea, 1, Loic Cerfb, 1, Benjamin Dehayc, d, 1, Paula Ramos-Gonzaleza, Francesca De Giorgic, d, e, Mathieu Bourdenxc, d, Alban Bessedeb, Jose A. Obesof, Carlos Matutea, 2, François Ichasc, d, e, 2, Erwan Bezardc, d, g, , 2, a 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 b ImmuSmol, F-33600 Pessac, France c Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France d CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France e INSERM U1084 Laboratoire de Neurosciences Experimentales et Cliniques, F-86000 Poitiers, France f HM Centro Integral de Neurociencias A.C. (CINAC), HM Puerta del Sur and CIBERNED and CEU-San Pablo University Madrid, E-28938 Mostoles, Spain g Motac Neuroscience, UK-M15 6WE Manchester, UK Received 12 January 2017, Revised 7 April 2017, Accepted 10 April 2017, Available online 11 April 2017