title: α-synuclein and synapsin III cooperatively regulate synaptic function in dopamine neurons.
abstract: The main neuropathological features of Parkinson's disease are dopaminergic nigrostriatal neuron degeneration, and intraneuronal and intraneuritic proteinaceous inclusions named Lewy bodies and Lewy neurites, respectively, which mainly contain α-synuclein (α-syn, also known as SNCA). The neuronal phosphoprotein synapsin III (also known as SYN3), is a pivotal regulator of dopamine neuron synaptic function. Here, we show that α-syn interacts with and modulates synapsin III. The absence of α-syn causes a selective increase and redistribution of synapsin III, and changes the organization of synaptic vesicle pools in dopamine neurons. In α-syn-null mice, the alterations of synapsin III induce an increased locomotor response to the stimulation of synapsin-dependent dopamine overflow, despite this, these mice show decreased basal and depolarization-dependent striatal dopamine release. Of note, synapsin III seems to be involved in α-syn aggregation, which also coaxes its increase and redistribution. Furthermore, synapsin III accumulates in the caudate and putamen of individuals with Parkinson's disease. These findings support a reciprocal modulatory interaction of α-syn and synapsin III in the regulation of dopamine neuron synaptic function.
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, 25123, Brescia, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Zaltieri
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, 25123, Brescia, Italy.
authors.forename: Jessica
authors.initials: J
authors.lastname: Grigoletto
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, 25123, Brescia, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Longhena
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, 25123, Brescia, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Navarria
authors.affiliation: Department of Clinical and Experimental Sciences, University of Brescia, 25123, Brescia, Italy.
authors.forename: Gaia
authors.initials: G
authors.lastname: Favero
authors.affiliation: Department of Clinical and Experimental Sciences, University of Brescia, 25123, Brescia, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Castrezzati
authors.affiliation: NEUROFARBA Department, University of Florence, 50139, Florence, Italy.
authors.forename: Maria Alessandra
authors.initials: MA
authors.lastname: Colivicchi
authors.affiliation: NEUROFARBA Department, University of Florence, 50139, Florence, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Della Corte
authors.affiliation: Department of Clinical and Experimental Sciences, University of Brescia, 25123, Brescia, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Rezzani
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, 25123, Brescia, Italy Neurorehabilitation Unit, IRCCS San Camillo Hospital (NHS-Italy), 30126, Venice Lido, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Pizzi
authors.affiliation: Department of Neuroscience and Brain Technologies, 16163, Italian Institute of Technology, Genoa, Italy Department of Experimental Medicine, University of Genoa, 16132, Genoa, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Benfenati
authors.affiliation: Department of Clinical Neuroscience, The Clifford Allbutt Building, University of Cambridge, Cambridge CB2 0QH, UK.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Spillantini
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, 25123, Brescia, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Missale
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, 25123, Brescia, Italy Neurorehabilitation Unit, IRCCS San Camillo Hospital (NHS-Italy), 30126, Venice Lido, Italy.
authors.forename: PierFranco
authors.initials: P
authors.lastname: Spano
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, 25123, Brescia, Italy arianna.bellucci@unibs.it.
authors.forename: Arianna
authors.initials: A
authors.lastname: Bellucci
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage; D003342:Corpus Striatum; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000648:ultrastructure; D020868:Gene Silencing; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009043:Motor Activity; D050505:Mutant Proteins / Q000378:metabolism; D010300:Parkinson Disease; D017729:Presynaptic Terminals; D066329:Protein Aggregates; D011485:Protein Binding; D011699:Putamen; D013347:Subcellular Fractions / Q000378:metabolism; D013569:Synapses / Q000378:metabolism* / Q000648:ultrastructure; D016704:Synapsins / Q000378:metabolism*; D013572:Synaptic Vesicles / Q000378:metabolism; D051844:alpha-Synuclein / Q000172:deficiency / Q000378:metabolism*
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D050505:Mutant Proteins; D066329:Protein Aggregates; D016704:Synapsins; D051844:alpha-Synuclein; D003042:Cocaine; D004298:Dopamine
keywords: Dopamine release; Parkinson's disease; Synapsin III; Synaptic vesicles; α-synuclein