A53T-alpha-synuclein overexpression impairs dopamine signaling and striatal synaptic plasticity in old mice.

PloS One
Alexander KurzSuzana Gispert

Abstract

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. 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-PC...Continue Reading

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May 29, 2014·The Journal of Clinical Investigation·Guoxiang LiuHuaibin Cai
Dec 28, 2011·Journal of Neural Transmission·Jie LiBenshu Zhang
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Datasets Mentioned

BETA
GSE20547

Methods Mentioned

BETA
transgenic
electron microscopy
chips
gene trap
in vitro transcription
X-ray
PCR
infrared microscopy

Software Mentioned

Limma
GCOS
Prism
R
Spotfire Decision Site for
Affymetrix
TotalLab
Clampfit
Affy
Multigauge FujiFilm

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