Selective deficits in the expression of striatal-enriched mRNAs in Huntington’s disease Paula A. Desplats,* Kristi E. Kass,* Tim Gilmartin, Gregg D. Stanwood,à Elliott L. Woodward,* Steven R. Head, J. Gregor Sutcliffe* and Elizabeth A. Thomas* *Department of Molecular Biology and  Department of Research Services, The Scripps Research Institute, La Jolla, California, USA àVanderbilt Kennedy Center for Research on Human Development and Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA Abstract We have identified and cataloged 54 genes that exhibit pre- dominant expression in the striatum. Our hypothesis is that such mRNA molecules are likely to encode proteins that are preferentially associated with particular physiological proces- ses intrinsic to striatal neurons, and therefore might contribute to the regional specificity of neurodegeneration observed in striatal disorders such as Huntington’s disease (HD). Expression of these genes was measured simultaneously in the striatum of HD R6/1 transgenic mice using Affymetrix oligonucleotide arrays. We found a decrease in expression of 81% of striatum-enriched genes in HD transgenic mice. Changes in expression of genes associated with G-protein signaling and calcium homeostasis were highlighted. The most striking decrement was observed for a newly identified subunit of the sodium channel, beta 4, with dramatic decrea- ses in expression beginning at 8 weeks of age. A subset of striatal genes was tested by real-time PCR in caudate sam- ples from human HD patients. Similar alterations in expression were observed in human HD and the R6/1 model for the striatal genes tested. Expression of 15 of the striatum- enriched genes was measured in 6-hydroxydopamine- lesioned rats to determine their dependence on dopamine innervation. No changes in expression were observed for any of these genes. These findings demonstrate that mutant huntingtin protein causes selective deficits in the expression of mRNAs responsible for striatum-specific physiology and these may contribute to the regional specificity of degeneration observed in HD. Keywords: gene expression, human, in situ hybridization, neurodegeneration, R6/ 1, striatum. J. Neurochem. (2006) 96, 743–757. The striatum (consisting of the caudate nucleus and putamen) is the largest and major receptive component of the basal ganglia, a group of subcortical nuclei that include the substantia nigra, globus pallidus and the subthalamic nucleus. The basal ganglia act via multiple intrinsic and extrinsic circuits to control motor and cognitive functions (Parent 1990; Graybiel 1995). The striatum exhibits complex patterns of neurochemical and neuroanatomical connectivity and compartmentalization, and is critically involved in the generation of directed motor behaviors through highly specialized output pathways (Graybiel 1995). Proper dynamic regulation of cellular signaling in the striatum is the key to its specific functions. Disruption of this complex balance can have detrimental consequences, as observed in Huntington’s disease (HD) and Parkinson’s disease (PD), two devastating neurodegenerative disorders affecting intrinsic striatal neu- rons, and the dopaminergic input to the striatum, respectively. Received June 14, 2005; revised manuscript received October 6, 2005; accepted October 7, 2005. Address correspondence and reprint requests to Elizabeth A. Thomas, Department of Molecular Biology, MB-10, The Scripps Research Insti- tute, 10550 N. Torrey Pines Road, La Jolla, CA, USA. E-mail: bthomas@scripps.edu Abbreviations used: ACV, adenylate cyclase V; Ct, threshold cycle; DARPP32, dopamine and c-AMP regulated phosphoprotein of 32 kDA; GPR22, G protein coupled receptor 22; HD, Huntington’s disease; 5HT2, 5-hydroxytryptamine receptor 2; IRSp53, insulin receptor substrate protein-53; ISL1, islet activating factor 1; KCNIP1, Kv chan- nel-interacting protein 2; MBA, mouse brain anatomy; 6-OHDA, 6-hy- droxydopamine; OSBPL-8, oxysterol binding protein like-8; PMI, postmortem interval; PD, Parkinson’s disease; PDE, phosphodiesterase; RGS9, regulator of G-protein signaling-9; Rhes, ras homolog enriched in striatum; RXR, retinoid X receptor; SCNb4, sodium channel subunit beta 4; SSC, saline-sodium citrate buffer; STEP61, striatal enriched phosphatase 61. Journal of Neurochemistry , 2006, 96, 743–757 doi:10.1111/j.1471-4159.2005.03588.x Ó 2006 The authors Journal Compilation Ó 2006 International Society for Neurochemistry, J. Neurochem. (2006) 96, 743–757 743