TY  - JOUR
A1  - Kurz, Alexander
A1  - Double, Kay L.
A1  - Lastres-Becker, Isabel
A1  - Tozzi, Alessandro
A1  - Tantucci, Michela
A1  - Bockhart, Vanessa
A1  - Bonin, Michael
A1  - García-Arencibia, Moisés
A1  - Nuber, Silke
A1  - Schlaudraff, Falk
A1  - Liss, Birgit
A1  - Fernández-Ruiz, Javier
A1  - Gerlach, Manfred
A1  - Wüllner, Ullrich
A1  - Lüddens, Hartmut
A1  - Calabresi, Paolo
A1  - Auburger, Georg
A1  - Gispert, Suzana
T1  - A53T-alpha-synuclein overexpression impairs dopamine signaling and striatal synaptic plasticity in old mice
T2  - PLoS One
N2  - 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.
Y1  - 2010
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/20232
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30-84718
SN  - 1932-6203
N1  - Copyright: © 2010 Kurz et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
VL  - 5
IS  - (7): e11464
ER  -