Phosphodiesterase 10A (PDE10A) localization in the R6/2 mouse model of Huntington's disease

Alessandro Leuti, Daunia Laurenti, Carmela Giampà, Elena Montagna, Clemente Dato, Serenella Anzilotti, Mariarosa A B Melone, Giorgio Bernardi, Francesca R. Fusco

Research output: Contribution to journalArticle

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Abstract

In Huntington's disease (HD) mutant huntingtin protein impairs the function of several transcription factors, in particular the cAMP response element-binding protein (CREB). CREB activation can be increased by targeting phosphodiesterases such as phospohodiesterase 4 (PDE4) and phosphodiesterase 10A (PDE10A). Indeed, both PDE4 inhibition (DeMarch et al., 2008) and PDE10A inhibition (Giampà et al., 2010) proved beneficial in the R6/2 mouse model of HD. However, Hebb et al. (2004) reported PDE10A decline in R6/2 mice. These findings raise the issue of how PDE10A inhibition is beneficial in HD if such enzyme is lost.R6/2 mice and their wild type littermates were treated with the PDE10A inhibitor TP10 (a gift from Pfizer) or saline, sacrificed at 5, 9, and 13. weeks of age, and single and double label immunohistochemistry and western blotting were performed. PDE10A increased dramatically in the spiny neurons of R6/2 compared to the wild type mice. Conversely, in the striatal cholinergic interneurons, PDE10A was lower and it did not change significantly with disease progression. In the other subsets of striatal interneurons (namely, parvalbuminergic, somatostatinergic, and calretininergic interneurons) PDE10A immunoreactivity was higher in the R6/2 compared to the wild-type mice. In the TP10 treated R6/2, PDE10A levels were lower than in the saline treated mice in the medium spiny neurons, whereas they were higher in all subsets of striatal interneurons except for the cholinergic ones. However, in the whole striatum densitometry studies, PDE10A immunoreactivity was lower in the R6/2 compared to the wild-type mice.Our study demonstrates that PDE10A is increased in the spiny neurons of R6/2 mice striatum. Thus, the accumulation of PDE10A in the striatal projection neurons, by hydrolyzing greater amounts of cyclic nucleotides, is likely to contribute to cell damage in HD. Consequently, the beneficial effect of TP10 in HD models (Giampà et al., 2009, 2010) is explained by the efficiency of such compound in counteracting this phenomenon and therefore increasing the availability of cyclic nucleotides.

Original languageEnglish
Pages (from-to)104-116
Number of pages13
JournalNeurobiology of Disease
Volume52
DOIs
Publication statusPublished - Apr 2013

Fingerprint

Huntington Disease
Phosphoric Diester Hydrolases
Corpus Striatum
Interneurons
Neurons
Cyclic AMP Response Element-Binding Protein
Cyclic Nucleotides
Cholinergic Agents
Type 4 Cyclic Nucleotide Phosphodiesterase
Gift Giving
Phosphodiesterase Inhibitors
Densitometry
Mutant Proteins
Disease Progression
Transcription Factors
Western Blotting
Immunohistochemistry
Efficiency

Keywords

  • Huntington's disease
  • Immunohistochemistry
  • PDE10A
  • Striatum

ASJC Scopus subject areas

  • Neurology

Cite this

Phosphodiesterase 10A (PDE10A) localization in the R6/2 mouse model of Huntington's disease. / Leuti, Alessandro; Laurenti, Daunia; Giampà, Carmela; Montagna, Elena; Dato, Clemente; Anzilotti, Serenella; Melone, Mariarosa A B; Bernardi, Giorgio; Fusco, Francesca R.

In: Neurobiology of Disease, Vol. 52, 04.2013, p. 104-116.

Research output: Contribution to journalArticle

Leuti, Alessandro ; Laurenti, Daunia ; Giampà, Carmela ; Montagna, Elena ; Dato, Clemente ; Anzilotti, Serenella ; Melone, Mariarosa A B ; Bernardi, Giorgio ; Fusco, Francesca R. / Phosphodiesterase 10A (PDE10A) localization in the R6/2 mouse model of Huntington's disease. In: Neurobiology of Disease. 2013 ; Vol. 52. pp. 104-116.
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