Cell-Produced α-Synuclein Is Secreted in a Calcium-Dependent Manner by Exosomes and Impacts Neuronal Survival

By Evangelia Emmanouilidou, Katerina Melachroinou, T. Roumeliotis, S. Garbis, M. Ntzouni, L. Margaritis, Leonidas Stefanis, K. Vekrellis. Journal of Neuroscience, 2010

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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.

Subfields: Cellular and Molecular Neuroscience, Neurology, Polymers and Plastics

View Paper: https://www.semanticscholar.org/paper/70673a893c825ea5cf08feb7ba657b2c5ded0c6f

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Citations in the corpus

Extracellular vesicles: Exosomes, microvesicles, and friends (2013, background): “…pathogenic proteins that are involved in central nervous system diseases, such as prions (Fevrier et al., 2004), -amyloid peptide (Rajendran et al., 2006), superoxide dismutase (Gomes et al., 2007), and -synuclein (Emmanouilidou et al., 2010), are released from cells in association with EVs.”
A new pathway for mitochondrial quality control: mitochondrial‐derived vesicles (2014, background): “Secretion and cell-to-cell transfer of a-synuclein has been shown both in cells and in vivo (Lee et al, 2004, 2005, 2008a,b; Desplats et al, 2009; Luk et al, 2012a,b), and exosomes constitute a proposed method of propagation (Emmanouilidou et al, 2010; Kong et al, 2014; Lee et al, 2014).”
α-Synuclein in Parkinson's disease. (2012, background): “…of a-synuclein secretion is not well understood, but it appears to occur through a nonclassical secretory pathway (Lee et al. 2005), possibly within exosomes, endocytic vesicles that are contained within multivesicular bodies and are released on calcium influx (Emmanouilidou et al. 2010b).”
Prion-like spreading of pathological α-synuclein in brain (2013, background): “Recent studies have also shown that exogenous -synuclein fibrils induced Lewy body pathology in cultured neurons (Desplats et al., 2009; Emmanouilidou et al., 2010; Nonaka et al., 2010; Volpicelli-Daley et al., 2011), transgenic mouse brain (Mougenot et al.”
Mitochondrial dysfunction in Parkinson's disease: molecular mechanisms and pathophysiological consequences (2012, positive): “…diffusion, endocytosis, and exosome-mediated uptake have been observed, and it is highly likely that the mode of cell entry depends on the type of a -synuclein species to be taken up (Sung et al , 2001; Desplats et al , 2009; Park et al , 2009; Emmanouilidou et al , 2010; Hansen et al , 2011).”
Neuroinflammation Induces Neurodegeneration (2016, background): “EVs contribute to the development of neuroinflammatory and neuropathological disorders in the CNS [95,96].”
Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice (2012, background): “…Syn species from dying neurons or by exocytosis represents a more probable source of transmissible Syn (Lee et al., 2008; Desplats et al., 2009; Emmanouilidou et al., 2010; Danzer et al., 2011; Hansen et al., 2011), uptake of which may trigger a reiterative patho genic process like the one…”
α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. (2011, positive): “Additionally, α -syn monomers and aggregates can be released from cultured cells by exocytosis (20, 23) and exosomes have been suggested to participate in this process (24).”