title: A53T-alpha-synuclein overexpression impairs dopamine signaling and striatal synaptic plasticity in old mice.
abstract: BACKGROUND
  Parkinson's disease (PD), the second most frequent neurodegenerative disorder at old age, can be caused by elevated expression or the A53T missense mutation of the presynaptic protein alpha-synuclein (SNCA). PD is characterized pathologically by the preferential vulnerability of the dopaminergic nigrostriatal projection neurons.
  
  
  RESULTS
  Here, we used two mouse lines overexpressing human A53T-SNCA and studied striatal dysfunction in the absence of neurodegeneration to understand early disease mechanisms. To characterize the progression, we employed young adult as well as old mice. Analysis of striatal neurotransmitter content demonstrated that dopamine (DA) levels correlated directly with the level of expression of SNCA, an observation also made in SNCA-deficient (knockout, KO) mice. However, the elevated DA levels in the striatum of old A53T-SNCA overexpressing mice may not be transmitted appropriately, in view of three observations. First, a transcriptional downregulation of the extraneural DA degradation enzyme catechol-ortho-methytransferase (COMT) was found. Second, an upregulation of DA receptors was detected by immunoblots and autoradiography. Third, extensive transcriptome studies via microarrays and quantitative real-time RT-PCR (qPCR) of altered transcript levels of the DA-inducible genes Atf2, Cb1, Freq, Homer1 and Pde7b indicated a progressive and genotype-dependent reduction in the postsynaptic DA response. As a functional consequence, long term depression (LTD) was absent in corticostriatal slices from old transgenic mice.
  
  
  CONCLUSIONS
  Taken together, the dysfunctional neurotransmission and impaired synaptic plasticity seen in the A53T-SNCA overexpressing mice reflect early changes within the basal ganglia prior to frank neurodegeneration. As a model of preclinical stages of PD, such insights may help to develop neuroprotective therapeutic approaches.
authors.affiliation: Department of Neurology, Goethe University Medical School, Frankfurt, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kurz
authors.forename: Kay L
authors.initials: KL
authors.lastname: Double
authors.forename: Isabel
authors.initials: I
authors.lastname: Lastres-Becker
authors.forename: Alessandro
authors.initials: A
authors.lastname: Tozzi
authors.forename: Michela
authors.initials: M
authors.lastname: Tantucci
authors.forename: Vanessa
authors.initials: V
authors.lastname: Bockhart
authors.forename: Michael
authors.initials: M
authors.lastname: Bonin
authors.forename: Moisés
authors.initials: M
authors.lastname: García-Arencibia
authors.forename: Silke
authors.initials: S
authors.lastname: Nuber
authors.forename: Falk
authors.initials: F
authors.lastname: Schlaudraff
authors.forename: Birgit
authors.initials: B
authors.lastname: Liss
authors.forename: Javier
authors.initials: J
authors.lastname: Fernández-Ruiz
authors.forename: Manfred
authors.initials: M
authors.lastname: Gerlach
authors.forename: Ullrich
authors.initials: U
authors.lastname: Wüllner
authors.forename: Hartmut
authors.initials: H
authors.lastname: Lüddens
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabresi
authors.forename: Georg
authors.initials: G
authors.lastname: Auburger
authors.forename: Suzana
authors.initials: S
authors.lastname: Gispert
mesh_terms: D051698:Activating Transcription Factor 2 / Q000235:genetics; D000375:Aging / Q000235:genetics / Q000502:physiology; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000378:metabolism*; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7 / Q000235:genetics; D004298:Dopamine / Q000378:metabolism*; D004594:Electrophysiology; D000072233:Homer Scaffolding Proteins; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D051580:Neuronal Calcium-Sensor Proteins / Q000235:genetics; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology*; D009479:Neuropeptides / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D015531:Radioimmunoprecipitation Assay; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051698:Activating Transcription Factor 2; C497106:Atf2 protein, mouse; D002352:Carrier Proteins; C000606614:HOMER1 protein, human; D000072233:Homer Scaffolding Proteins; C000606623:Homer1 protein, mouse; D051580:Neuronal Calcium-Sensor Proteins; D009479:Neuropeptides; D043884:Receptor, Cannabinoid, CB1; D051844:alpha-Synuclein; C101464:frequenin calcium sensor proteins; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7; C517465:Pde7b protein, mouse; D004298:Dopamine