A53T-Alpha-Synuclein Overexpression Impairs Dopamine Signaling and Striatal Synaptic Plasticity in Old Mice
| العنوان: | A53T-Alpha-Synuclein Overexpression Impairs Dopamine Signaling and Striatal Synaptic Plasticity in Old Mice |
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| المؤلفون: | Alexander Kurz, Manfred Gerlach, Ullrich Wüllner, Birgit Liss, Michael Bonin, Paolo Calabresi, Hartmut Lüddens, Vanessa Bockhart, Kay L. Double, Suzana Gispert, Isabel Lastres-Becker, Alessandro Tozzi, Michela Tantucci, Javier Fernández-Ruiz, Georg Auburger, Silke Nuber, Falk Schlaudraff, Moisés García-Arencibia |
| المصدر: | PLoS ONE PLoS ONE, Vol 5, Iss 7, p e11464 (2010) |
| بيانات النشر: | Public Library of Science (PLoS), 2010. |
| سنة النشر: | 2010 |
| مصطلحات موضوعية: | Aging, Dopamine, lcsh:Medicine, Mice, chemistry.chemical_compound, Homer Scaffolding Proteins, Receptor, Cannabinoid, CB1, lcsh:Science, Long-term depression, Neurotransmitter, Chromatography, High Pressure Liquid, In Situ Hybridization, Fluorescence, Oligonucleotide Array Sequence Analysis, Mice, Knockout, Neuronal Plasticity, Multidisciplinary, Reverse Transcriptase Polymerase Chain Reaction, Dopaminergic, Neurodegeneration, Genetics and Genomics/Gene Expression, Electrophysiology, alpha-Synuclein, Research Article, Radioimmunoprecipitation Assay, medicine.medical_specialty, Neuronal Calcium-Sensor Proteins, HOMER1, Substantia nigra, Neurotransmission, Biology, Neurological Disorders, Internal medicine, medicine, Animals, Humans, ddc:610, Cyclic Nucleotide Phosphodiesterases, Type 7, Activating Transcription Factor 2, lcsh:R, Neuropeptides, medicine.disease, Molecular biology, Corpus Striatum, Mice, Mutant Strains, Endocrinology, Genetics and Genomics/Disease Models, chemistry, Synaptic plasticity, lcsh:Q, Carrier Proteins |
| الوصف: | 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. METHODOLOGY/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. CONCLUSIONS/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. |
| وصف الملف: | application/pdf |
| تدمد: | 1932-6203 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5acb911d6d2a82c64fc56270ea395adfTest https://doi.org/10.1371/journal.pone.0011464Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....5acb911d6d2a82c64fc56270ea395adf |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19326203 |
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