Phospholipase D1 downregulation by α-synuclein: Implications for neurodegeneration in Parkinson's disease |
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Authors: | Melisa A Conde Natalia P Alza Pablo A Iglesias González Paola G Scodelaro Bilbao Sofía Sánchez Campos Romina M Uranga Gabriela A Salvador |
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Institution: | 1. Instituto de Investigaciones Bioquímicas de Bahía Blanca (INIBIBB), Argentina;2. Departamento de Biología, Bioquímica y Farmacia-Universidad Nacional del Sur (UNS), Argentina;3. Departamento de Química-UNS, Argentina;4. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Bahía Blanca, Argentina |
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Abstract: | We have previously shown that phospholipase D (PLD) pathways have a role in neuronal degeneration; in particular, we found that PLD activation is associated with synaptic injury induced by oxidative stress. In the present study, we investigated the effect of α-synuclein (α-syn) overexpression on PLD signaling. Wild Type (WT) α-syn was found to trigger the inhibition of PLD1 expression as well as a decrease in ERK1/2 phosphorylation and expression levels. Moreover, ERK1/2 subcellular localization was shown to be modulated by WT α-syn in a PLD1-dependent manner. Indeed, PLD1 inhibition was found to alter the neurofilament network and F-actin distribution regardless of the presence of WT α-syn. In line with this, neuroblastoma cells expressing WT α-syn exhibited a degenerative-like phenotype characterized by a marked reduction in neurofilament light subunit (NFL) expression and the rearrangement of the F-actin organization, compared with either the untransfected or the empty vector-transfected cells. The gain of function of PLD1 through the overexpression of its active form had the effect of restoring NFL expression in WT α-syn neurons. Taken together, our findings reveal an unforeseen role for α-syn in PLD regulation: PLD1 downregulation may constitute an early mechanism in the initial stages of WT α-syn-triggered neurodegeneration. |
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Keywords: | α-syn alpha synuclein AU arbitrary units cytosolic fraction DAG diacylglycerol ERK extracellular signal-regulated kinase ev IMR-32 cell line stably transfected with pcDNA empty vector IMR32 human neuroblastoma cell line LW Lewy bodies MAPKs mitogen-activated protein kinases MEK MAPK kinase NF nuclear fraction NFH neurofilament heavy subunit NFL neurofilament light subunit NFM neurofilament medium subunit PA phosphatidic acid PD Parkinson's disease PEth phosphatidylethanol PKC protein kinase C PLD phospholipase D PLD1i specific pharmacological PLD1 inhibitor PLD2i specific pharmacological PLD2 inhibitor qRT-PCR quantitative real-time polymerase chain reaction ut IMR-32 untransfected cells WT wild type WT α-syn IMR-32 cell line overexpressing human wild type α-syn Phospholipase D1 α-Synuclein Neurofilament Phosphatidic acid Neurodegeneration Parkinson's disease |
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