RT Journal Article
SR Electronic
T1 Cell-Produced α-Synuclein Is Secreted in a Calcium-Dependent Manner by Exosomes and Impacts Neuronal Survival
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 6838
OP 6851
DO 10.1523/JNEUROSCI.5699-09.2010
VO 30
IS 20
A1 Evangelia Emmanouilidou
A1 Katerina Melachroinou
A1 Theodoros Roumeliotis
A1 Spiros D. Garbis
A1 Maria Ntzouni
A1 Lukas H. Margaritis
A1 Leonidas Stefanis
A1 Kostas Vekrellis
YR 2010
UL http://www.jneurosci.org/content/30/20/6838.abstract
AB α-Synuclein is central in Parkinson's disease pathogenesis. Although initially α-synuclein was considered a purely intracellular protein, recent data suggest that it can be detected in the plasma and CSF of humans and in the culture media of neuronal cells. To address a role of secreted α-synuclein in neuronal homeostasis, we have generated wild-type α-synuclein and β-galactosidase inducible SH-SY5Y cells. Soluble oligomeric and monomeric species of α-synuclein are readily detected in the conditioned media (CM) of these cells at concentrations similar to those observed in human CSF. We have found that, in this model, α-synuclein is secreted by externalized vesicles in a calcium-dependent manner. Electron microscopy and liquid chromatography–mass spectrometry proteomic analysis demonstrate that these vesicles have the characteristic hallmarks of exosomes, secreted intraluminar vesicles of multivesicular bodies. Application of CM containing secreted α-synuclein causes cell death of recipient neuronal cells, which can be reversed after α-synuclein immunodepletion from the CM. High- and low-molecular-weight α-synuclein species, isolated from this CM, significantly decrease cell viability. Importantly, treatment of the CM with oligomer-interfering compounds before application rescues the recipient neuronal cells from the observed toxicity. Our results show for the first time that cell-produced α-synuclein is secreted via an exosomal, calcium-dependent mechanism and suggest that α-synuclein secretion serves to amplify and propagate Parkinson's disease-related pathology.