title: GRP78 clustering at the cell surface of neurons transduces the action of exogenous alpha-synuclein.
abstract: Mutation or multiplication of the alpha-synuclein (Syn)-encoding gene is frequent cause of early onset Parkinson's disease (PD). Recent evidences point to the pathogenic role of excess Syn also in sporadic PD. Syn is a cytosolic protein, which has been shown to be released from neurons. Here we provide evidence that extracellular Syn induces an increase in surface-exposed glucose-related protein of 78 kDa (GRP78), which becomes clustered in microdomains of the neuronal plasma membrane. Upon interacting with Syn, GRP78 activates a signaling cascade leading to cofilin 1 inactivation and stabilization of microfilaments, thus affecting morphology and dynamics of actin cytoskeleton in cultured neurons. Downregulation of GRP78 abolishes the activity of exogenous Syn, indicating that it is the primary target of Syn. Inactivation of cofilin 1 and stabilization of actin cytoskeleton are present also in fibroblasts derived from genetic PD patients, which show a dramatic increase in stress fibers. Similar changes are displayed by control cells incubated with the medium of PD fibroblasts, only when Syn is present. The accumulation of Syn in the extracellular milieu, its interaction with the plasma membrane and Syn-driven clustering of GRP78 appear, therefore, responsible for the dysregulation of actin turnover, leading to early deficits in synaptic function that precede neurodegeneration.
authors.affiliation: Division of Neuroscience, San Raffaele Scientific Institute and Vita-Salute University, Milan 20132, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Bellani
authors.affiliation: Department of Nanophysics and Brain Technologies, Istituto Italiano di Tecnologia, Genoa 16163, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Mescola
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa 16163, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Ronzitti
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa 16163, Italy.
authors.forename: H
authors.initials: H
authors.lastname: Tsushima
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa 16163, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Tilve
authors.affiliation: Department of Nanophysics and Brain Technologies, Istituto Italiano di Tecnologia, Genoa 16163, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Canale
authors.affiliation: Division of Neuroscience, San Raffaele Scientific Institute and Vita-Salute University, Milan 20132, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Valtorta
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genoa 16163, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Chieregatti
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D051338:Cofilin 1 / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D055550:Protein Stability; D021381:Protein Transport; D015398:Signal Transduction; D051844:alpha-Synuclein / Q000502:physiology*
chemical_list: D051338:Cofilin 1; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D051844:alpha-Synuclein