Phosphodiesterase 10A (PDE10A) localization in the R6/2 mouse model of Huntington's disease
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 phosphodiesteras...
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| Format: | Article |
| Language: | English |
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Elsevier
2013-04-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996112003798 |
| _version_ | 1819120133656805376 |
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| author | Alessandro Leuti Daunia Laurenti Carmela Giampà Elena Montagna Clemente Dato Serenella Anzilotti Mariarosa A.B. Melone Giorgio Bernardi Francesca R. Fusco |
| author_facet | Alessandro Leuti Daunia Laurenti Carmela Giampà Elena Montagna Clemente Dato Serenella Anzilotti Mariarosa A.B. Melone Giorgio Bernardi Francesca R. Fusco |
| author_sort | Alessandro Leuti |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T06:15:49Z |
| format | Article |
| id | doaj.art-36225fd1227b475694e3d1da237ea91b |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-22T06:15:49Z |
| publishDate | 2013-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-36225fd1227b475694e3d1da237ea91b2022-12-21T18:36:05ZengElsevierNeurobiology of Disease1095-953X2013-04-0152104116Phosphodiesterase 10A (PDE10A) localization in the R6/2 mouse model of Huntington's diseaseAlessandro Leuti0Daunia Laurenti1Carmela Giampà2Elena Montagna3Clemente Dato4Serenella Anzilotti5Mariarosa A.B. Melone6Giorgio Bernardi7Francesca R. Fusco8Laboratory of Neuroanatomy, Santa Lucia Foundation IRCCS Hospital, Rome, ItalyLaboratory of Neuroanatomy, Santa Lucia Foundation IRCCS Hospital, Rome, ItalyLaboratory of Neuroanatomy, Santa Lucia Foundation IRCCS Hospital, Rome, ItalyLaboratory of Neuroanatomy, Santa Lucia Foundation IRCCS Hospital, Rome, ItalyLaboratory of Neuroanatomy, Santa Lucia Foundation IRCCS Hospital, Rome, ItalyLaboratory of Neuroanatomy, Santa Lucia Foundation IRCCS Hospital, Rome, ItalyDivision of Neurology, Department of Clinical and Experimental Medicine and Surgery, Second University of Naples, Naples, Italy; Institute of Protein Biochemistry, CNR, Naples, ItalyLaboratory of Neuroanatomy, Santa Lucia Foundation IRCCS Hospital, Rome, Italy; Department of Neuroscience, University of Rome Tor Vergata, Rome, ItalyLaboratory of Neuroanatomy, Santa Lucia Foundation IRCCS Hospital, Rome, Italy; Corresponding author at: Laboratory of Neuroanatomy, Santa Lucia Foundation IRCCS Hospital, Via del Fosso Fiorano 64, 00179 Rome, Italy. Fax: +39 00 5150 1581.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.http://www.sciencedirect.com/science/article/pii/S0969996112003798Huntington's diseasePDE10AStriatumImmunohistochemistry |
| spellingShingle | Alessandro Leuti Daunia Laurenti Carmela Giampà Elena Montagna Clemente Dato Serenella Anzilotti Mariarosa A.B. Melone Giorgio Bernardi Francesca R. Fusco Phosphodiesterase 10A (PDE10A) localization in the R6/2 mouse model of Huntington's disease Neurobiology of Disease Huntington's disease PDE10A Striatum Immunohistochemistry |
| title | Phosphodiesterase 10A (PDE10A) localization in the R6/2 mouse model of Huntington's disease |
| title_full | Phosphodiesterase 10A (PDE10A) localization in the R6/2 mouse model of Huntington's disease |
| title_fullStr | Phosphodiesterase 10A (PDE10A) localization in the R6/2 mouse model of Huntington's disease |
| title_full_unstemmed | Phosphodiesterase 10A (PDE10A) localization in the R6/2 mouse model of Huntington's disease |
| title_short | Phosphodiesterase 10A (PDE10A) localization in the R6/2 mouse model of Huntington's disease |
| title_sort | phosphodiesterase 10a pde10a localization in the r6 2 mouse model of huntington s disease |
| topic | Huntington's disease PDE10A Striatum Immunohistochemistry |
| url | http://www.sciencedirect.com/science/article/pii/S0969996112003798 |
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