title: GABA transmission via ATP-dependent K+ channels regulates α-synuclein secretion in mouse striatum.
abstract: α-Synuclein is readily released in human and mouse brain parenchyma, even though the normal function of the secreted protein has not been yet elucidated. Under pathological conditions, such as in Parkinson's disease, pathologically relevant species of α-synuclein have been shown to propagate between neurons in a prion-like manner, although the mechanism by which α-synuclein transfer induces degeneration remains to be identified. Due to this evidence extracellular α-synuclein is now considered a critical target to hinder disease progression in Parkinson's disease. Given the importance of extracellular α-synuclein levels, we have now investigated the molecular pathway of α-synuclein secretion in mouse brain. To this end, we have identified a novel synaptic network that regulates α-synuclein release in mouse striatum. In this brain area, the majority of α-synuclein is localized in corticostriatal glutamatergic terminals. Absence of α-synuclein from the lumen of brain-isolated synaptic vesicles suggested that they are unlikely to mediate its release. To dissect the mechanism of α-synuclein release, we have used reverse microdialysis to locally administer reagents that locally target specific cellular pathways. Using this approach, we show that α-synuclein secretion in vivo is a calcium-regulated process that depends on the activation of sulfonylurea receptor 1-sensitive ATP-regulated potassium channels. Sulfonylurea receptor 1 is distributed in the cytoplasm of GABAergic neurons from where the ATP-dependent channel regulates GABA release. Using a combination of specific agonists and antagonists, we were able to show that, in the striatum, modulation of GABA release through the sulfonylurea receptor 1-regulated ATP-dependent potassium channels located on GABAergic neurons controls α-synuclein release from the glutamatergic terminals through activation of the presynaptic GABAB receptors. Considering that sulfonylurea receptors can be selectively targeted, our study highlights the potential use of the key molecules in the α-synuclein secretory pathway to aid the discovery of novel therapeutic interventions for Parkinson's disease.
authors.affiliation: 1 Department of Neuroscience, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece eemman@bioacademy.gr.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Emmanouilidou
authors.affiliation: 2 Erlangen-Nürnberg (FAU), University Hospital Erlangen, Department of Molecular Neurology, Erlangen 91054, Germany.
authors.forename: Georgia
authors.initials: G
authors.lastname: Minakaki
authors.affiliation: 1 Department of Neuroscience, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece.
authors.forename: Maria V
authors.initials: MV
authors.lastname: Keramioti
authors.affiliation: 1 Department of Neuroscience, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece.
authors.forename: Mary
authors.initials: M
authors.lastname: Xylaki
authors.affiliation: 3 Laboratory Animal Facilities, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Balafas
authors.affiliation: 4 Reasearch Unit of Histochemistry and Electron Microscopy, 1st Department of Psychiatry, University of Athens Medical School, Eginition Hospital, Athens 11528, Greece.
authors.forename: Margarita
authors.initials: M
authors.lastname: Chrysanthou-Piterou
authors.affiliation: 5 Theodor Theohari Cozzika Foundation, Neurobiology Research Institute, Athens 11521, Greece 6 Center of Basic Research, Biomedical Research Foundation, Academy of Athens, Athens 11527, Greece.
authors.forename: Ismini
authors.initials: I
authors.lastname: Kloukina
authors.affiliation: 1 Department of Neuroscience, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens 11527, Greece.
authors.forename: Kostas
authors.initials: K
authors.lastname: Vekrellis
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D018757:GABA Modulators / Q000494:pharmacology; D006801:Humans; D054086:KATP Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018080:Receptors, GABA-B / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D051844:alpha-Synuclein / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018757:GABA Modulators; D054086:KATP Channels; D018080:Receptors, GABA-B; C497604:SNCA protein, human; D051844:alpha-Synuclein; D005680:gamma-Aminobutyric Acid
keywords: KATP channels; SUR1; reverse microdialysis; secretion; striatum; α-synuclein