Elsevier

Neuroscience

Volume 123, Issue 4, 2004, Pages 967-981
Neuroscience

Striatal phosphodiesterase mRNA and protein levels are reduced in Huntington′s disease transgenic mice prior to the onset of motor symptoms

https://doi.org/10.1016/j.neuroscience.2003.11.009Get rights and content

Abstract

Inheritance of a single copy of the gene encoding huntingtin (HD) with an expanded polyglutamine-encoding CAG repeat leads to neuronal dysfunction, neurodegeneration and the development of the symptoms of Huntington's disease (HD). We have found that the steady-state mRNA levels of two members of the phosphodiesterase (PDE) multi-gene family decrease over time in the striatum of R6 transgenic HD mice relative to age-matched wild-type littermates. Phosphodiesterase 10A (PDE10A) mRNA and protein levels decline in the striatum of R6/1 and R6/2 HD mice prior to motor symptom development. The rate of reduction in PDE10A protein correlates with the rate of decline of the message and the decrease in PDE10A mRNA and protein is more rapid in R6/2 compared with R6/1 mice. Both PDE10A protein and mRNA, therefore, decline to minimum levels prior to the onset of overt physical symptoms in both strains of transgenic mice. Moreover, protein levels of PDE10A are decreased in the caudate-putamen of grade 3 HD patients compared with age-matched neuropathologically normal controls. Striatal PDE1B mRNA levels also decline in R6/1 and R6/2 HD mice; however, the decrease in striatal PDE10A levels (>60%) was greater than that observed for PDE1B and immediately preceded the onset of motor symptoms. In contrast, PDE4A mRNA levels are relatively low in the striatum and do not differ between age-matched wild-type and transgenic HD mice. This suggests that the regulation of PDE10A and PDE1B, but not PDE4A, mRNA levels is dependent on the relative expression of or number of CAG repeats within the human HD transgene. The loss of phosphodiesterase activity may lead to dysregulation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) levels in the striatum, a region of the brain that contributes to the control of movement and cognition.

Section snippets

Animals and tissue samples

A colony of R6/1 and R6/2 transgenic HD mice was established and maintained by crossing hemizygous carrier R6/2 or R6/1 males with CBA×C57BL/6 females. All mice were originally purchased from The Jackson Laboratory (Bar Harbor, ME, USA). Mice were genotyped by amplifying a region of the human HD transgene using primers 5′ AGG GCGT GTC AAT CAT GCT GG 3′ and 5′ GGA CTT GAG GGA CTC GAA 3′. These primers correspond to a region upstream of the CAG repeat at nucleotides 77–96 and 347–364,

Differential display analysis of striatal RNA derived from WT and transgenic HD mice

Studies using DNA microarray profiling have previously identified a number of differences in gene expression in the striatum of WT and transgenic HD mice (Luthi-Carter et al., 2000). The objective of this study was to identify changes in the expression of genes that were not included in the microarray-based analyses. We employed differential display RT-PCR (Denovan-Wright et al., 2000) to identify differences in the patterns of gene expression between the striatum of WT and R6/2 transgenic mice

Discussion

PDE10A is a recently described member of the PDE multigene family that is unique from other PDEs with respect to amino acid sequence, tissue-specific pattern of expression, and affinity for cAMP and cyclic guanosine monophosphate (cGMP). PDE10A is a cAMP and cAMP-inhibited cGMP PDE that is highly expressed in regions of the brain that are innervated by dopaminergic neurons such as the striatum, nucleus accumbens and olfactory tubercle (Fujishige et al., 1999a,Fujishige et al., 1999b, Loughney

Conclusion

The expression of mutant HD leads to changes in the steady-state levels of a small proportion of mRNAs in the striatum (Cha et al., 1998, Denovan-Wright and Robertson, 2000, Cha, 2000, Luthi-Carter et al., 2000). Analysis of mRNA levels in transgenic HD mice has demonstrated that changes in the mRNA levels of PDE10A and PDE1B are dependent on the expression level and number of CAG repeats in the human HD transgene in HD mice and that the loss of PDE activity may contribute to dysregulation of

Acknowledgements

This research was supported by grants from the Canadian Institute of Health Research to Eileen M. Denovan-Wright and Harold A. Robertson. Andrea L. O. Hebb holds an industrial post-doctoral fellowship from the Canadian Institute of Health Research and Nova Neuron, Inc. We thank J. Nason, M. Huang, K. Stevens, L. Hamilton and K. Murphy for technical assistance. Human brain tissue was provided by the Harvard Brain Tissue Resource Center, which is supported in part by PHS grant number MH/NS 31862.

References (79)

  • T. Furuyama et al.

    Localization of 63 kDa calmodulin-stimulated phosphodiesterase mRNA in the rat brain by in situ hybridization histochemistry

    Mol Brain Res

    (1994)
  • K.B. Kegel et al.

    Huntingtin is present in the nucleus, interacts with the transcriptional corepressor C-terminal binding protein, and represses transcription

    J Biol Chem

    (2002)
  • Y.F. Liu

    Expression of polyglutamine-expanded Huntingtin activates the SEK1-JNK pathway and induces apoptosis in a hippocampal neuronal cell line

    J Biol Chem

    (1998)
  • K. Loughney et al.

    Isolation and characterization of PDE10A, a novel human 3′, 5′-cyclic nucleotide phosphodiesterase

    Gene

    (1999)
  • C.L. Ludlow et al.

    Speech timing in Parkinson's and Huntington's disease

    Brain Lang

    (1987)
  • L. Mangiarini et al.

    Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice

    Cell

    (1996)
  • R.B. Moreland et al.

    Sildenafil citrate, a selective phosphodiesterase 5 inhibitor

    Trends Endocrinol Metab

    (1999)
  • M.F. Perutz

    Glutamine repeats and inherited neurodegenerative diseasesmolecular aspects

    Curr Opin Struct Biol

    (1996)
  • E.K. Richfield et al.

    Heterogeneous dopamine receptor changes in early and late Huntington's disease

    Neurosci Lett

    (1991)
  • C.A. Ross

    When more is lesspathogenesis of glutamine repeat neurodegenerative diseases

    Neuron

    (1995)
  • A.H. Sharp et al.

    Widespread expression of Huntington's disease gene (IT15) protein product

    Neuron

    (1995)
  • S.H. Soderling et al.

    Regulation of cAMP and cGMP signalingnew phosphodiesterases and new functions

    Curr Opin Cell Biol

    (2000)
  • W.M. van Roon-Mom et al.

    Insoluble TATA-binding protein accumulation in Huntington's disease cortex

    Brain Res Mol Brain Res

    (2002)
  • W.C.G. van Staveren et al.

    The effects of phosphodiesterase inhibition on cyclic GMP and cyclic AMP accumulation in the hippocampus of the rat

    Brain Res

    (2001)
  • J. Velier et al.

    Wild-type and mutant huntingtins function in vesicle trafficking in the secretory and endocytic pathways

    Exp Neurol

    (1998)
  • K. Zhang et al.

    Ontogeny of rolipram-sensitive, low-Km, cyclic AMP-specific phosphodiesterase in rat brain

    Dev Brain Res

    (1999)
  • K. Zhang et al.

    Effects of noradrenergic lesions on the development of rolipram-sensitive, low-Km, cyclic AMP-specific phosphodiesterase in rat brain

    Dev Brain Res

    (1999)
  • C.M. Ambrose et al.

    Structure and expression of the Huntington's disease geneevidence agonist simple inactivation due to an expanded CAG repeat

    Somat Cell Mol Genet

    (1994)
  • A. Barbeau

    Progress in understanding Huntington's chorea

    Can J Neurol Sci

    (1975)
  • J. Beavo

    Cyclic nucleotide phosphodiesterasefunctional implications of multiple isoforms

    Physiol Rev

    (1995)
  • P.G. Bhide et al.

    Expression of normal and mutant huntingtin in the developing brain

    J Neurosci

    (1996)
  • M. Boolell et al.

    Sildenafilan orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction

    Int J Impot Res

    (1996)
  • C. Bowes et al.

    Retinal degeneration in the rd mouse is caused by a defect in the B subunit of rod cGMP-phosphodiesterase

    Nature

    (1990)
  • E.D. Caine et al.

    Huntington's dementiaclinical and neuropsychological features

    Arch Gen Psychiatry

    (1978)
  • R.J. Carter et al.

    Characterization of progressive motor deficits in mice transgenic for the human Huntington's disease mutation

    J Neurosci

    (1999)
  • J.-H. Cha et al.

    Altered brain neurotransmitter receptors in transgenic mice expressing a portion of an abnormal human huntington disease gene

    Proc Natl Acad Sci USA

    (1998)
  • R.A. Challiss et al.

    Effects of selective phosphodiesterase inhibition on cyclic AMP hydrolysis in rat cerebral cortical slices

    Br J Pharm

    (1990)
  • J.T. Coyle

    An animal model of Huntington's disease

    Biol Psychiatry

    (1979)
  • Denovan-Wright EM, Gilby KL, Howlett SE, Robertson HA (2000) PCR 5: differential display: a practical approach. In:...
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