title: Elevated levels of alpha-synuclein blunt cellular signal transduction downstream of Gq protein-coupled receptors.
abstract: Alpha-synuclein is central to Parkinson's disease pathogenesis and pathology, however its precise functions are still unclear. It has been shown to bind both PLCβ1 and MAPKs, but how this property influences the downstream signaling of Gq protein-coupled receptors has not been elucidated. Here we show that recombinant expression of alpha-synuclein in human neuroblastoma cells enhances cellular levels of PLCβ1 but blunts its signaling pathway, preventing the agonist-dependent rise of cytoplasmic Ca2+. In addition, overexpressing alpha-synuclein abolishes the activation of ERK1/2 upon agonist stimulation, indicating an upstream action in the signal transduction pathway. This data demonstrates that alpha-synuclein, when recombinantly expressed, interferes with the normal signaling of Gq-protein coupled receptors, which are then dysfunctional. Since many neurotransmitter systems utilize these receptor signaling pathways to mediate different abilities affected in Parkinson's disease, we argue this novel perspective might be helpful in designing treatment strategies for some of the non-motor symptoms in Parkinson's disease and synucleinopathies.
authors.affiliation: Center for Biomedicine, EURAC Research, Via Galvani 31, Bolzano 39100, Italy(1). Electronic address: mattia.volta@eurac.edu.
authors.forename: Mattia
authors.initials: M
authors.lastname: Volta
authors.affiliation: Center for Biomedicine, EURAC Research, Via Galvani 31, Bolzano 39100, Italy(1).
authors.forename: Alexandros A
authors.initials: AA
authors.lastname: Lavdas
authors.affiliation: Center for Biomedicine, EURAC Research, Via Galvani 31, Bolzano 39100, Italy(1).
authors.forename: Julia
authors.initials: J
authors.lastname: Obergasteiger
authors.affiliation: Center for Biomedicine, EURAC Research, Via Galvani 31, Bolzano 39100, Italy(1).
authors.forename: Christa
authors.initials: C
authors.lastname: Überbacher
authors.affiliation: Center for Biomedicine, EURAC Research, Via Galvani 31, Bolzano 39100, Italy(1).
authors.forename: Anne
authors.initials: A
authors.lastname: Picard
authors.affiliation: Center for Biomedicine, EURAC Research, Via Galvani 31, Bolzano 39100, Italy(1).
authors.forename: Peter P
authors.initials: PP
authors.lastname: Pramstaller
authors.affiliation: Center for Biomedicine, EURAC Research, Via Galvani 31, Bolzano 39100, Italy(1).
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Hicks
authors.affiliation: Center for Biomedicine, EURAC Research, Via Galvani 31, Bolzano 39100, Italy(1). Electronic address: corrado.corti@eurac.edu.
authors.forename: Corrado
authors.initials: C
authors.lastname: Corti
mesh_terms: D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D006801:Humans; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism; D054799:Phospholipase C beta / Q000378:metabolism; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D011994:Recombinant Proteins; D051844:alpha-Synuclein; D048049:Extracellular Signal-Regulated MAP Kinases; D054799:Phospholipase C beta; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D002118:Calcium
keywords: Alpha-synuclein; Calcium; ERK1/2; Gq protein-coupled receptors; PLCβ1