Opposite changes of Phosphodiesterase-10A in striato-pallidal and striato-entopeduncular pathways of TorsinA DYT1 transgenic mice
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1
University of Rome Tor Vergata, Dept of Systems Medicine, Italy
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2
University of Rome La Sapienza, Dept of Biology and Biotechnology, Italy
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3
Foundation Santa Lucia, Italy
In most forms of dystonia the brain regions primary affected are thought to have functional rather than structural abnormalities. We report that changes of Phosphodiesterase-10A (PDE10A) immunoreactivity can map the involvement of the basal ganglia pathways in TorsinA DYT1 transgenic model. PDE10A, a key enzyme in the catabolism of cAMP and cGMP, has unique distribution in the basal ganglia, within medium spiny neurons in the striatum, and in their axons/terminals to the direct and indirect pathway, i.e. to the entopeduncular nucleus and external globus pallidus respectively. PDE10A was studied in control mice and in mice carrying either human wild-type torsinA or mutant torsinA.
Rabbit anti-PDE10A antibody was used for immunohistochemical identification of PDE10A neurons and nerve fibers. Quantitative analysis of PDE10A expression in the different brain areas was assessed by immunohistochemistry and Western blotting. Moreover, PDE10A dependent cAMP hydrolyzing activity was assessed.
Biochemical and morphological studies demonstrate that PDE10A expression and activity were clearly increased in the globus pallidus of mice carrying DYT1TorsinA mutation compared to control mice, while in the entopeduncular nucleus the PDE10A expression and activity were significantly decreased both in mice carrying wild-type human TorsinA and in mice carrying DYT1 TorsinA mutation. However, expression of PDE10A mRNA was comparable in the three groups of animals.
Our study demonstrates that PDE10A may act as translational biomarker of the pathophysiology of dystonia, involving the balance between the striato-pallidal and the striato-entopeduncular pathways, which could be investigated in vivo by novel PDE10A PET ligands.
References
Rostasy K, Augood SJ, Hewett JW, Leung JC, Sasaki H, Ozelius LJ, et al. TorsinA protein and neuropathology in early onset generalized dystonia with GAG deletion. Neurobiol Dis 2003;12:11-24.
Keywords:
Dystonia,
TorsinA,
Basal Ganglia,
PDE10A,
Cyclic AMP
Conference:
5th Biennial Workshop on Dystonia: “Controversies in Dystonia and Parkinsonism” | Nobile Collegio Chimico Farmaceutico, Rome, May 29-30, 2015, Rome, Italy, 29 May - 30 May, 2015.
Presentation Type:
Poster presentation
Topic:
Dystonia
Citation:
D'Angelo
V,
Castelli
V,
Saverioni
I,
Cardarelli
S,
Palumbo
F,
Giorgi
M,
Martorana
A,
Bonsi
P,
Pisani
A and
Sancesario
G
(2015). Opposite changes of Phosphodiesterase-10A in striato-pallidal and striato-entopeduncular pathways of TorsinA DYT1 transgenic mice.
Front. Neurol.
Conference Abstract:
5th Biennial Workshop on Dystonia: “Controversies in Dystonia and Parkinsonism” | Nobile Collegio Chimico Farmaceutico, Rome, May 29-30, 2015.
doi: 10.3389/conf.fneur.2015.57.00007
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Received:
30 Apr 2015;
Published Online:
01 May 2015.
*
Correspondence:
Prof. Giuseppe Sancesario, University of Rome Tor Vergata, Dept of Systems Medicine, Rome, 00133, Italy, sancesario@med.uniroma2.it