A53T-Alpha-Synuclein Overexpression Impairs Dopamine Signaling and Striatal Synaptic Plasticity in Old Mice

Alexander Kurz,Birgit Liss,Kay L Double,Falk Schlaudraff,Ullrich Wüllner,Hartmut Lüddens,Manfred Gerlach,Vanessa Bockhart,Silke Nuber,Paolo Calabresi,Alessandro Tozzi,Georg Auburger,Javier Fernández-Ruiz,Suzana Gispert,Michael Bonin,Michela Tantucci,Isabel Lastres-Becker,Moisés García-Arencibia,Michael J Pazin

doi:10.1371/journal.pone.0011464

Abstract

BackgroundParkinson'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 FindingsHere, 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/SignificanceTaken 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.

Highlights

Alpha-synuclein (SNCA) is a soluble, natively unfolded 17 kDa protein, which acquires an antiparallel conformation after binding to phospholipid surfaces
Counts of tyrosine hydroxylase (TH) positive dopaminergic neurons in consecutive sections throughout the entire substantia nigra (SN) of PrPmtA, PrPmtB or KO animals did not demonstrate any significant differences in nigral neuron numbers
These data are in agreement with our previous findings of a lack of neurodegeneration during the life span of our A53T-SNCA overexpressing mice [13] and suggest that these animals represent a milder form or an earlier stage of pathology compared with other SNCA-overexpressing mouse models which exhibit progressive striatal nerve terminal loss and dopaminergic axon degeneration [14,15,16]

Summary

Introduction

Alpha-synuclein (SNCA) is a soluble, natively unfolded 17 kDa protein, which acquires an antiparallel conformation after binding to phospholipid surfaces. Its abundant expression in neurons and the selective localization to nerve terminals point to an important role for signaling and synaptic maintenance. SNCA missense mutations, such as A53T, as well as increased expression of wild-type (WT) SNCA result in rare forms of Parkinson’s disease (PD) characterized by early-onset and autosomal dominant inheritance [3,4]. Undefined factors trigger the aggregation of WT-SNCA within neurites and the cytoplasm of degenerating neurons to form so-called Lewy bodies and Lewy neurites which are microscopically visible in most variants of PD, provoking the concept that SNCA oligomerization plays a key role in the neurodegenerative cascade [5]. 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

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Results

Conclusion