Emmanouilidou, E.

Melachroinou, K.

Papazafiri, P.

Stefanis, L.

Vekrellis, K.

Xilouri, M.

Digital Repository of Hellenic Managing Authority of the Operational Programme &quot;Education and Lifelong Learning&quot; (EDULLL)

DYSREGULATION OF Ca2+ HOMEOSTASIS CONTRIBUTES TO EXTRACELLULAR α-SYNUCLEIN-MEDIATED TOXICITY  Melachroinou K.1, Xilouri M.1, Emmanouilidou E.1, Papazafiri P. 2, Stefanis L.1,3, and Vekrellis K.1 1Division of Basic Neuroscience, Biomedical Research Foundation of the Academy of Athens 2Dept. of Animal and Human Physiology, National and Kapodistrian University of Athens 3Second Department of Neurology, University of Athens Medical School, Athens, Greece  α-Synuclein (AS) is an abundant presynaptic neuronal protein genetically and biochemically linked to Parkinson’s disease (PD) pathogenesis. Data from our laboratory and others suggest that AS can be normally secreted from neuronal cells. To assess the effects of secreted AS on neuronal homeostasis, we have used SH-SY5Y cells inducibly expressing human wild-type AS, as a source of naturally secreted AS. We have shown that these cells readily secrete AS species into their culture medium, partly via an exosome-mediated manner. Secreted AS forms were shown to be toxic to recipient neuronal cells. To investigate the possible mechanisms involved in the extracellular AS-mediated toxicity, we applied naturally secreted AS to differentiated SH-SY5Y cells. Our results show that such treatment alters Ca2+ homeostasis in recipient neuronal cells, manifested by increased capacitative Ca2+ entry, i.e. Ca2+ influx upon depletion of intracellular Ca2+ stores with thapsigargin (Tg). This effect was AS-dependent, since immunodepletion of the protein from the conditioned medium (CM) abolished Ca2+ influx. Importantly, the observed Ca2+ rise was attributed mainly to exosome-associated AS, given the fact that cells pretreated with exosomes isolated from AS-containing CM exhibited higher Ca2+ influx compared to cells recipient of exosome-depleted CM. Voltage Operated Ca2+ Channels (VOCs) were involved in the elevated cytosolic Ca2+ rise, since the use of specific inhibitors ameliorated AS-induced Ca2+ influx. Differentiated neuroblastoma cells incubated either with VOC blockers or with extracellular or intracellular Ca2+ chelators were resistant to secreted AS-mediated toxicity. Collectively, our data suggest that secreted AS, and particularly its exosomal component, is toxic to recipient neuronal cells through engagement, at least partly, of the intracellular Ca2+ homeostatic machinery. Manipulating Ca2+ signaling pathways mitigates extracellular AS toxicity and may therefore represent a potential therapeutic target for PD and related synucleinopathies.    8th Forum of European Neuroscience (FENS), 14-18 July 2012, Barcelona, Spain      

Dysregulation of Ca2+ homeostasis contributes to extracellular α-synuclein-mediated toxicity

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Dysregulation of Ca2+ homeostasis contributes to extracellular α-synuclein-mediated toxicity

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Digital Repository of Hellenic Managing Authority of the Operational Programme "Education and Lifelong Learning" (EDULLL)

Dysregulation of Ca2+ homeostasis contributes to extracellular α-synuclein-mediated toxicity

Abstract

Similar works

Full text

Available Versions

Digital Repository of Hellenic Managing Authority of the Operational Programme &quot;Education and Lifelong Learning&quot; (EDULLL)

Digital Repository of Hellenic Managing Authority of the Operational Programme "Education and Lifelong Learning" (EDULLL)