title: Overexpression of α-synuclein simultaneously increases glutamate NMDA receptor phosphorylation and reduces glucocerebrosidase activity.
abstract: Progressive accumulation of α-synuclein (α-syn)-containing protein aggregates throughout the nervous system is a pathological hallmark of Parkinson's disease (PD). The mechanisms whereby α-syn exerts neurodegeneration remain to be fully understood. Here we show that overexpression of α-syn in transgenic mice leads to increased phosphorylation of glutamate NMDA receptor (NMDAR) subunits NR1 and NR2B in substantia nigra and striatum as well as reduced glucocerebrosidase (GCase) levels. Similarly, molecular studies performed in mouse N2A cells stably overexpressing human α-syn ((α-syn)N2A) showed that phosphorylation states of the same NMDAR subunits were increased, whereas GCase levels and lysosomal GCase activity were reduced. (α-syn)N2A cells showed an increased sensitivity to neurotoxicity towards 6-hydroxydopamine and NMDA. However, wildtype N2A, but not (α-syn)N2A cells, showed a further reduction in viability when co-incubated with 6-hydroxydopamine and the lysosomal inhibitors NH4Cl and leupeptin, suggesting that α-syn per se perturbs lysosomal functions. NMDA treatment reduced lysosomal GCase activity to the same extent in (α-syn)N2A cells as in wildtype N2A cells, indicating that the α-syn-dependent difference in NMDA neurotoxicity is unrelated to an altered GCase activity. Nevertheless, these data provide molecular evidence that overexpression of α-syn simultaneously induces two potential neurotoxic hits by increasing glutamate NMDA receptor phosphorylation, consistent with increased NMDA receptors functionality, and reducing GCase activity.
authors.affiliation: Translational Neuropharmacology, Department of Clinical Neuroscience, Center for Molecular Medicine L8:01, Karolinska Institute, Stockholm 171 76, Sweden; Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300071, China.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Yang
authors.affiliation: Translational Neuropharmacology, Department of Clinical Neuroscience, Center for Molecular Medicine L8:01, Karolinska Institute, Stockholm 171 76, Sweden.
authors.forename: Ellen
authors.initials: E
authors.lastname: Hertz
authors.affiliation: Translational Neuropharmacology, Department of Clinical Neuroscience, Center for Molecular Medicine L8:01, Karolinska Institute, Stockholm 171 76, Sweden.
authors.forename: Xiaoqun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Translational Neuropharmacology, Department of Clinical Neuroscience, Center for Molecular Medicine L8:01, Karolinska Institute, Stockholm 171 76, Sweden.
authors.forename: Lina
authors.initials: L
authors.lastname: Leinartaité
authors.affiliation: Translational Neuropharmacology, Department of Clinical Neuroscience, Center for Molecular Medicine L8:01, Karolinska Institute, Stockholm 171 76, Sweden.
authors.forename: Ebba Gregorsson
authors.initials: EG
authors.lastname: Lundius
authors.affiliation: Department of Mental Health Center, Tianjin Medical University, 13 Liulin Road, Tianjin 300222, China. Electronic address: jieli@tmu.edu.cn.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Translational Neuropharmacology, Department of Clinical Neuroscience, Center for Molecular Medicine L8:01, Karolinska Institute, Stockholm 171 76, Sweden. Electronic address: per.svenningsson@ki.se.
authors.forename: Per
authors.initials: P
authors.lastname: Svenningsson
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D003342:Corpus Striatum / Q000378:metabolism; D018628:Gene Dosage; D005962:Glucosylceramidase / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016627:Oxidopamine / Q000633:toxicity; D010766:Phosphorylation; D021122:Protein Subunits / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013378:Substantia Nigra / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; D051844:alpha-Synuclein; D016627:Oxidopamine; D005962:Glucosylceramidase
keywords: Cytotoxicity; Glucocerebrosidase; NMDA; Parkinson’s disease; α-Synuclein