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