A53T-Alpha-Synuclein Overexpression Impairs Dopamine Signaling and Striatal Synaptic Plasticity in Old Mice
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{"title"=>"A53T-alpha-synuclein overexpression impairs dopamine signaling and striatal synaptic plasticity in old mice", "type"=>"journal", "authors"=>[{"first_name"=>"Alexander", "last_name"=>"Kurz", "scopus_author_id"=>"7101885394"}, {"first_name"=>"Kay L.", "last_name"=>"Double", "scopus_author_id"=>"6701343585"}, {"first_name"=>"Isabel", "last_name"=>"Lastres-Becker", "scopus_author_id"=>"6603353572"}, {"first_name"=>"Alessandro", "last_name"=>"Tozzi", "scopus_author_id"=>"7006852996"}, {"first_name"=>"Michela", "last_name"=>"Tantucci", "scopus_author_id"=>"6506479603"}, {"first_name"=>"Vanessa", "last_name"=>"Bockhart", "scopus_author_id"=>"35106701300"}, {"first_name"=>"Michael", "last_name"=>"Bonin", "scopus_author_id"=>"14007876300"}, {"first_name"=>"Moisés", "last_name"=>"García-Arencibia", "scopus_author_id"=>"15821889300"}, {"first_name"=>"Silke", "last_name"=>"Nuber", "scopus_author_id"=>"14822697200"}, {"first_name"=>"Falk", "last_name"=>"Schlaudraff", "scopus_author_id"=>"23994447000"}, {"first_name"=>"Birgit", "last_name"=>"Liss", "scopus_author_id"=>"7004106821"}, {"first_name"=>"Javier", "last_name"=>"Fernández-Ruiz", "scopus_author_id"=>"7006533053"}, {"first_name"=>"Manfred", "last_name"=>"Gerlach", "scopus_author_id"=>"7007083707"}, {"first_name"=>"Ullrich", "last_name"=>"Wullner", "scopus_author_id"=>"7007062470"}, {"first_name"=>"Hartmut", "last_name"=>"Lüddens", "scopus_author_id"=>"7006690125"}, {"first_name"=>"Paolo", "last_name"=>"Calabresi", "scopus_author_id"=>"7102418853"}, {"first_name"=>"Georg", "last_name"=>"Auburger", "scopus_author_id"=>"7005458571"}, {"first_name"=>"Suzana", "last_name"=>"Gispert", "scopus_author_id"=>"6701465933"}], "year"=>2010, "source"=>"PLoS ONE", "identifiers"=>{"pmid"=>"20628651", "doi"=>"10.1371/journal.pone.0011464", "sgr"=>"77955347330", "isbn"=>"1932-6203", "scopus"=>"2-s2.0-77955347330", "issn"=>"19326203", "pui"=>"359318630"}, "id"=>"7029f0fc-86fb-3ce2-b789-753db22ff367", "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.\\n\\nMETHODOLOGY/PRINCIPAL FINDINGS: 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.\\n\\nCONCLUSIONS/SIGNIFICANCE: 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.", "link"=>"http://www.mendeley.com/research/a53talphasynuclein-overexpression-impairs-dopamine-signaling-striatal-synaptic-plasticity-old-mice", "reader_count"=>107, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>6, "Researcher"=>34, "Student > Doctoral Student"=>4, "Student > Ph. D. Student"=>30, "Student > Postgraduate"=>1, "Student > Master"=>9, "Other"=>11, "Student > Bachelor"=>3, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>4}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>6, "Researcher"=>34, "Student > Doctoral Student"=>4, "Student > Ph. D. Student"=>30, "Student > Postgraduate"=>1, "Student > Master"=>9, "Other"=>11, "Student > Bachelor"=>3, "Lecturer"=>2, "Lecturer > Senior Lecturer"=>1, "Professor"=>4}, "reader_count_by_subject_area"=>{"Unspecified"=>4, "Engineering"=>2, "Biochemistry, Genetics and Molecular Biology"=>5, "Materials Science"=>1, "Agricultural and Biological Sciences"=>60, "Medicine and Dentistry"=>20, "Neuroscience"=>11, "Business, Management and Accounting"=>1, "Psychology"=>2, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>2}, "Materials Science"=>{"Materials Science"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>20}, "Neuroscience"=>{"Neuroscience"=>11}, "Psychology"=>{"Psychology"=>2}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>60}, "Computer Science"=>{"Computer Science"=>1}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Unspecified"=>{"Unspecified"=>4}}, "reader_count_by_country"=>{"Belgium"=>1, "United States"=>2, "United Kingdom"=>1, "Germany"=>3, "Spain"=>1}, "group_count"=>5}

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  • {"files"=>["https://ndownloader.figshare.com/files/419241", "https://ndownloader.figshare.com/files/419265", "https://ndownloader.figshare.com/files/419290", "https://ndownloader.figshare.com/files/419308", "https://ndownloader.figshare.com/files/419319", "https://ndownloader.figshare.com/files/419339"], "description"=>"<div><h3>Background</h3><p>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.</p><h3>Methodology/Principal Findings</h3><p>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-<em>ortho</em>-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 <em>Atf2</em>, <em>Cb<sub>1</sub></em>, <em>Freq</em>, <em>Homer1</em> and <em>Pde7b</em> 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.</p><h3>Conclusions/Significance</h3><p>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.</p></div>", "links"=>[], "tags"=>["a53t-alpha-synuclein", "overexpression", "impairs", "dopamine", "signaling", "striatal", "synaptic", "plasticity", "mice"], "article_id"=>142790, "categories"=>["Genetics", "Neuroscience"], "users"=>["Alexander Kurz", "Kay L. Double", "Isabel Lastres-Becker", "Alessandro Tozzi", "Michela Tantucci", "Vanessa Bockhart", "Michael Bonin", "Moisés García-Arencibia", "Silke Nuber", "Falk Schlaudraff", "Birgit Liss", "Javier Fernández-Ruiz", "Manfred Gerlach", "Ullrich Wüllner", "Hartmut Lüddens", "Paolo Calabresi", "Georg Auburger", "Suzana Gispert"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0011464.s001", "https://dx.doi.org/10.1371/journal.pone.0011464.s002", "https://dx.doi.org/10.1371/journal.pone.0011464.s003", "https://dx.doi.org/10.1371/journal.pone.0011464.s004", "https://dx.doi.org/10.1371/journal.pone.0011464.s005", "https://dx.doi.org/10.1371/journal.pone.0011464.s006"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/A53T_Alpha_Synuclein_Overexpression_Impairs_Dopamine_Signaling_and_Striatal_Synaptic_Plasticity_in_Old_Mice/142790", "title"=>"A53T-Alpha-Synuclein Overexpression Impairs Dopamine Signaling and Striatal Synaptic Plasticity in Old Mice", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2010-07-07 00:46:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/841273"], "description"=>"<p>Bar graphs depicting mRNA levels and protein levels of transgenic human A53T-alpha-synuclein. (A) Overexpressing mouse lines PrPmtA and PrPmtB exhibit similar mRNA levels of transgenic human A53T-alpha-synuclein in the midbrain at old age. (B) Accordingly, these mice show no differences in the protein levels of transgenic human A53T-alpha-synuclein in the striatum, the target area of the nigrostriatal projection. Data was normalized to the loading control (<i>Tbp</i> transcript or beta-actin protein) and to the mean values of PrPmtA mRNA or PrPmtA protein levels, respectively, and presented as bar graphs. N = 3 animals/genotype. “pc”  =  positive control (human brain protein medley/#635301, Clontech); “nc”  =  negative control (mouse brain extract/#sc-2253, Santa Cruz Biotechnology).</p>", "links"=>[], "tags"=>["a53t-alpha-synuclein", "mrna"], "article_id"=>511715, "categories"=>["Genetics", "Neuroscience"], "users"=>["Alexander Kurz", "Kay L. Double", "Isabel Lastres-Becker", "Alessandro Tozzi", "Michela Tantucci", "Vanessa Bockhart", "Michael Bonin", "Moisés García-Arencibia", "Silke Nuber", "Falk Schlaudraff", "Birgit Liss", "Javier Fernández-Ruiz", "Manfred Gerlach", "Ullrich Wüllner", "Hartmut Lüddens", "Paolo Calabresi", "Georg Auburger", "Suzana Gispert"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0011464.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Human_A53T_alpha_synuclein_mRNA_and_protein_expression_at_old_age_/511715", "title"=>"Human A53T-alpha-synuclein mRNA and protein expression at old age.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-07-07 00:28:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/841395"], "description"=>"<p>Bar graphs illustrating the dopamine levels in both A53T-SNCA overexpressing mouse lines (PrPmtA and PrPmtB), the alpha-synuclein-deficient line (KO) and corresponding wild-type (WT) animals analyzed in striatal tissue homogenates via HPLC. Increases of striatal dopamine (DA) levels were observed in young animals as a trend (A) and in old animals with high significance (B) for both A53T-SNCA overexpressing mouse lines. Correspondingly, in the SNCA-deficient (KO) mice, a smaller decrease of striatal DA levels was observed in young animals (C) which progressed in old KO animals (D). Statistical significance is reflected via asterisks (* p<0.05; ** p<0.01; *** p<0.001).</p>", "links"=>[], "tags"=>["levels", "striatal", "homogenates", "correlate", "snca"], "article_id"=>511830, "categories"=>["Genetics", "Neuroscience"], "users"=>["Alexander Kurz", "Kay L. Double", "Isabel Lastres-Becker", "Alessandro Tozzi", "Michela Tantucci", "Vanessa Bockhart", "Michael Bonin", "Moisés García-Arencibia", "Silke Nuber", "Falk Schlaudraff", "Birgit Liss", "Javier Fernández-Ruiz", "Manfred Gerlach", "Ullrich Wüllner", "Hartmut Lüddens", "Paolo Calabresi", "Georg Auburger", "Suzana Gispert"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0011464.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_DA_levels_in_striatal_homogenates_correlate_to_SNCA_expression_level_/511830", "title"=>"DA levels in striatal homogenates correlate to SNCA expression level.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-07-07 00:30:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/841545"], "description"=>"<p>Bar graph illustrating the reduced transcript levels for the extraneural dopamine degradation enzyme catechol-<i>ortho</i>-methyltransferase (<i>Comt</i>) in the striatum of both A53T-SNCA overexpressing mouse lines (PrPmtA and PrPmtB). Statistical significance is reflected via asterisks (** p<0.01; *** p<0.001). Expression changes were analyzed with the 2<sup>−ΔΔCt</sup> method <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0011464#pone.0011464-LastresBecker1\" target=\"_blank\">[52]</a>.</p>", "links"=>[], "tags"=>["transcript", "levels", "striata", "transgenic", "lines"], "article_id"=>511986, "categories"=>["Genetics", "Neuroscience"], "users"=>["Alexander Kurz", "Kay L. Double", "Isabel Lastres-Becker", "Alessandro Tozzi", "Michela Tantucci", "Vanessa Bockhart", "Michael Bonin", "Moisés García-Arencibia", "Silke Nuber", "Falk Schlaudraff", "Birgit Liss", "Javier Fernández-Ruiz", "Manfred Gerlach", "Ullrich Wüllner", "Hartmut Lüddens", "Paolo Calabresi", "Georg Auburger", "Suzana Gispert"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0011464.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Reduced_Comt_transcript_levels_in_striata_of_both_transgenic_lines_at_old_age_/511986", "title"=>"Reduced <i>Comt</i> transcript levels in striata of both transgenic lines at old age.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-07-07 00:33:06"}
  • {"files"=>["https://ndownloader.figshare.com/files/841630"], "description"=>"<p>Increased levels of DRD1A in lines PrPmtA (A; 1.63-fold; p<0.0001; 3 mice/genotype; slices: WT n = 39, PrPmtA n = 38) and PrPmtB (E; 1.34-fold; p<0.0001; 2 mice/genotype; slices: WT n = 44, PrPmtA n = 40), as well as increased levels of DRD2 in lines PrPmtA (B; 1.48-fold; p<0.0001; 3 mice/genotype; slices: WT n = 35, PrPmtA n = 36) and PrPmtB (F; 1.13-fold; p<0.034; 2 mice/genotype; slices: WT n = 30, PrPmtA n = 25) were observed at old age. Independent data validation was successful in immunoblot experiments employing striatal protein extracts of old PrPmtA mice for DRD1A (C; 1.88-fold; p = 0.001; WT n = 4, PrPmtA n = 4) and DRD2 (D; 1.92-fold; p = 0.004; WT n = 4, PrPmtA n = 4) normalized to the beta-actin/GAPDH loading control, while the elevation did not reach significance for PrPmtB derived samples (data not shown). Student's t-test was employed for all statistical analyses. PSL  =  photo-stimulated luminescence; pc  =  positive control (mouse brain extract/#sc-2253, Santa Cruz Biotechnology). Statistical significance is reflected via asterisks (* p<0.05; ** p<0.01; *** p<0.001).</p>", "links"=>[], "tags"=>["immunoblot", "elevated", "striatal", "drd1a", "drd2"], "article_id"=>512065, "categories"=>["Genetics", "Neuroscience"], "users"=>["Alexander Kurz", "Kay L. Double", "Isabel Lastres-Becker", "Alessandro Tozzi", "Michela Tantucci", "Vanessa Bockhart", "Michael Bonin", "Moisés García-Arencibia", "Silke Nuber", "Falk Schlaudraff", "Birgit Liss", "Javier Fernández-Ruiz", "Manfred Gerlach", "Ullrich Wüllner", "Hartmut Lüddens", "Paolo Calabresi", "Georg Auburger", "Suzana Gispert"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0011464.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Autoradiography_and_immunoblot_reveal_elevated_striatal_DRD1A_and_DRD2_levels_/512065", "title"=>"Autoradiography and immunoblot reveal elevated striatal DRD1A and DRD2 levels.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-07-07 00:34:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/841837"], "description"=>"<p><i>In situ</i> hybridization and receptor autoradiography in A53T-SNCA overexpressing versus WT mice at old age show decreased levels of the cannabinoid receptor 1 (<i>Cb<sub>1</sub></i>) mRNA in striatum (A; white arrow) and of CB<sub>1</sub> protein in the substantia nigra (B; white arrow) as well as the globus pallidus (C; white arrow). Scale bar: 1 mm.</p>", "links"=>[], "tags"=>["transcript"], "article_id"=>512283, "categories"=>["Genetics", "Neuroscience"], "users"=>["Alexander Kurz", "Kay L. Double", "Isabel Lastres-Becker", "Alessandro Tozzi", "Michela Tantucci", "Vanessa Bockhart", "Michael Bonin", "Moisés García-Arencibia", "Silke Nuber", "Falk Schlaudraff", "Birgit Liss", "Javier Fernández-Ruiz", "Manfred Gerlach", "Ullrich Wüllner", "Hartmut Lüddens", "Paolo Calabresi", "Georg Auburger", "Suzana Gispert"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0011464.g005"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Decreased_Cb_1_expression_on_transcript_and_protein_level_/512283", "title"=>"Decreased Cb<sub>1</sub> expression on transcript and protein level.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-07-07 00:38:03"}
  • {"files"=>["https://ndownloader.figshare.com/files/841994"], "description"=>"<p>Voltage traces of striatal medium spiny neurons (MSNs) recorded in whole-cell patch-clamp during hyperpolarizing and depolarizing steps of current. Note the similar firing pattern discharge in the representative WT, PrPmtA and PrPmtB neuron (A). Graph showing a similar input-output curve of striatal field potential (FP) evoked by 200 µsec stimuli of increasing voltage intensities applied on corticostriatal fibers in WT, PrPmtA and PrPmtB mice (B). Representative examples of corticostriatal FP acquired 10 min before high frequency stimulation (HFS) protocol and 40 min after HFS in WT, PrPmtA and PrPmtB mice (C). Time-course of FP amplitudes showing the induction of LTD only in WT mice, whereas no long-lasting change of the FP amplitude in PrPmtA and PrPmtB mice is monitored up to 40 min following the HFS protocol application (D). The significance level was established at p<0.001 (**) and p<0.0001 (***).</p>", "links"=>[], "tags"=>["demonstrates", "absent", "corticostriatal", "slices"], "article_id"=>512437, "categories"=>["Genetics", "Neuroscience"], "users"=>["Alexander Kurz", "Kay L. Double", "Isabel Lastres-Becker", "Alessandro Tozzi", "Michela Tantucci", "Vanessa Bockhart", "Michael Bonin", "Moisés García-Arencibia", "Silke Nuber", "Falk Schlaudraff", "Birgit Liss", "Javier Fernández-Ruiz", "Manfred Gerlach", "Ullrich Wüllner", "Hartmut Lüddens", "Paolo Calabresi", "Georg Auburger", "Suzana Gispert"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0011464.g006"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Electrophysiological_analysis_demonstrates_absent_long_term_depression_LTD_in_corticostriatal_slices_of_old_mice_/512437", "title"=>"Electrophysiological analysis demonstrates absent long term depression (LTD) in corticostriatal slices of old mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-07-07 00:40:37"}
  • {"files"=>["https://ndownloader.figshare.com/files/842094"], "description"=>"<p>This schematic illustration summarizes the progressive pathology of a striatal MSN dendritic spine. The MSN is innervated by nigrostriatal dopaminergic input where the presence of pathogenic overexpressed A53T-SNCA causes elevated presynaptic DA. In glia cells, the DA degradation enzyme COMT is transcriptionally downregulated, suggesting altered extracellular turnover of DA. Postsynaptically, the upregulation of DRD1A and DRD2 and the decreased transcript levels of several DA-inducible genes suggest a progressively diminishing striatal DA response. In parallel, the plasticity of corticostriatal glutamatergic synapses is affected through retrograde signaling, leading to the absence of LTD.</p>", "links"=>[], "tags"=>["progressively", "abnormal", "synaptic", "signaling", "a53t-snca"], "article_id"=>512532, "categories"=>["Genetics", "Neuroscience"], "users"=>["Alexander Kurz", "Kay L. Double", "Isabel Lastres-Becker", "Alessandro Tozzi", "Michela Tantucci", "Vanessa Bockhart", "Michael Bonin", "Moisés García-Arencibia", "Silke Nuber", "Falk Schlaudraff", "Birgit Liss", "Javier Fernández-Ruiz", "Manfred Gerlach", "Ullrich Wüllner", "Hartmut Lüddens", "Paolo Calabresi", "Georg Auburger", "Suzana Gispert"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0011464.g007"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Synopsis_of_progressively_abnormal_synaptic_signaling_in_old_A53T_SNCA_striata_/512532", "title"=>"Synopsis of progressively abnormal synaptic signaling in old A53T-SNCA striata.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-07-07 00:42:12"}

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  • {"unique-ip"=>"15", "full-text"=>"13", "pdf"=>"3", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"4", "supp-data"=>"14", "cited-by"=>"0", "year"=>"2016", "month"=>"10"}
  • {"unique-ip"=>"11", "full-text"=>"13", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"8", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"11"}
  • {"unique-ip"=>"7", "full-text"=>"8", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"12"}
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  • {"unique-ip"=>"16", "full-text"=>"15", "pdf"=>"3", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"11"}
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  • {"unique-ip"=>"21", "full-text"=>"25", "pdf"=>"3", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"6", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"3"}
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  • {"unique-ip"=>"16", "full-text"=>"17", "pdf"=>"5", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"6"}
  • {"unique-ip"=>"18", "full-text"=>"15", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"3", "cited-by"=>"0", "year"=>"2018", "month"=>"7"}
  • {"unique-ip"=>"16", "full-text"=>"16", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2018", "month"=>"8"}
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  • {"unique-ip"=>"24", "full-text"=>"25", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"12"}
  • {"unique-ip"=>"26", "full-text"=>"26", "pdf"=>"8", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"11"}
  • {"unique-ip"=>"14", "full-text"=>"18", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"9"}
  • {"unique-ip"=>"35", "full-text"=>"39", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"2"}
  • {"unique-ip"=>"21", "full-text"=>"23", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"10", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2019", "month"=>"3"}
  • {"unique-ip"=>"25", "full-text"=>"29", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"4"}
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Relative Metric

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