title: Redistribution of DAT/α-synuclein complexes visualized by "in situ" proximity ligation assay in transgenic mice modelling early Parkinson's disease.
abstract: Alpha-synuclein, the major component of Lewy bodies, is thought to play a central role in the onset of synaptic dysfunctions in Parkinson's disease (PD). In particular, α-synuclein may affect dopaminergic neuron function as it interacts with a key protein modulating dopamine (DA) content at the synapse: the DA transporter (DAT). Indeed, recent evidence from our "in vitro" studies showed that α-synuclein aggregation decreases the expression and membrane trafficking of the DAT as the DAT is retained into α-synuclein-immunopositive inclusions. This notwithstanding, "in vivo" studies on PD animal models investigating whether DAT distribution is altered by the pathological overexpression and aggregation of α-synuclein are missing. By using the proximity ligation assay, a technique which allows the "in situ" visualization of protein-protein interactions, we studied the occurrence of alterations in the distribution of DAT/α-synuclein complexes in the SYN120 transgenic mouse model, showing insoluble α-synuclein aggregates into dopaminergic neurons of the nigrostriatal system, reduced striatal DA levels and an altered distribution of synaptic proteins in the striatum. We found that DAT/α-synuclein complexes were markedly redistributed in the striatum and substantia nigra of SYN120 mice. These alterations were accompanied by a significant increase of DAT striatal levels in transgenic animals when compared to wild type littermates. Our data indicate that, in the early pathogenesis of PD, α-synuclein acts as a fine modulator of the dopaminergic synapse by regulating the subcellular distribution of key proteins such as the DAT.
authors.affiliation: Division of Pharmacology, Department of Biomedical Sciences and Biotechnologies and National Institute of Neuroscience-Italy, School of Medicine, University of Brescia, Brescia, Italy. bellucci@med.unibs.it
authors.forename: Arianna
authors.initials: A
authors.lastname: Bellucci
authors.forename: Laura
authors.initials: L
authors.lastname: Navarria
authors.forename: Elisa
authors.initials: E
authors.lastname: Falarti
authors.forename: Michela
authors.initials: M
authors.lastname: Zaltieri
authors.forename: Federica
authors.initials: F
authors.lastname: Bono
authors.forename: Ginetta
authors.initials: G
authors.lastname: Collo
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Spillantini
authors.forename: Maria
authors.initials: M
authors.lastname: Grazia
authors.forename: Cristina
authors.initials: C
authors.lastname: Missale
authors.forename: Pierfranco
authors.initials: P
authors.lastname: Spano
mesh_terms: D000818:Animals; D003042:Cocaine / Q000494:pharmacology; D003342:Corpus Striatum / Q000502:physiology; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D011485:Protein Binding; D013378:Substantia Nigra / Q000502:physiology; D014162:Transfection; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D051844:alpha-Synuclein; D003042:Cocaine; D005947:Glucose; D004298:Dopamine