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The Journal of Neuroscience, September 24, 2008, 28(39):9723-9731; doi:10.1523/JNEUROSCI.3044-08.2008
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Brief Communications
Dysregulation of Gene Expression in Primary Neuron Models of Huntington's Disease Shows That Polyglutamine-Related Effects on the Striatal Transcriptome May Not Be Dependent on Brain Circuitry
Heike Runne,1 Etienne Régulier,1 Alexandre Kuhn,1 Diana Zala,1 Ozgun Gokce,1 Valérie Perrin,1 Beate Sick,2 Patrick Aebischer,1 Nicole Déglon,1,3 andRuth Luthi-Carter1 1Laboratory of Functional Neurogenomics, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, 2Lausanne DNA Array Facility and Swiss Institute of Bioinformatics, University of Lausanne, CH-1015 Lausanne, Switzerland, and 3Commissariat à Energie Atomique, Institute of Biomedical Imaging and Molecular Imaging Research Center, 91401 Orsay Cedex, France
Correspondence should be addressed to Ruth Luthi-Carter, Laboratory of Functional Neurogenomics, AI2138 Station 15, Brain Mind Institute, Faculty of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland. Email: ruth.luthi-carter{at}epfl.ch
Gene expression changes are a hallmark of the neuropathology of Huntington's disease (HD), but the exact molecular mechanisms of this effect remain uncertain. Here, we report that in vitro models of disease comprised of primary striatal neurons expressing N-terminal fragments of mutant huntingtin (via lentiviral gene delivery) faithfully reproduce the gene expression changes seen in human HD. Neither viral infection nor unrelated (enhanced green fluorescent protein) transgene expression had a major effect on resultant RNA profiles. Expression of a wild-type fragment of huntingtin [htt171-18Q] also caused only a small number of RNA changes. The disease-related signal in htt171-82Q versus htt171-18Q comparisons was far greater, resulting in the differential detection of 20% of all mRNA probe sets. Transcriptomic effects of mutated htt171 are time- and polyglutamine-length dependent and occur in parallel with other manifestations of polyglutamine toxicity over 4–8 weeks. Specific RNA changes in htt171-82Q-expressing striatal cells accurately recapitulated those observed in human HD caudate and included decreases in PENK (proenkephalin), RGS4 (regulator of G-protein signaling 4), dopamine D1 receptor (DRD1), DRD2, CNR1 (cannabinoid CB1 receptor), and DARPP-32 (dopamine- and cAMP-regulated phosphoprotein-32; also known as PPP1R1B) mRNAs. HD-related transcriptomic changes were also observed in primary neurons expressing a longer fragment of mutant huntingtin (htt853-82Q). The gene expression changes observed in cultured striatal neurons are not secondary to abnormalities of neuronal firing or glutamatergic, dopaminergic, or brain-derived neurotrophic factor signaling, thereby demonstrating that HD-induced dysregulation of the striatal transcriptome might be attributed to intrinsic effects of mutant huntingtin.
Key words: polyglutamine disease; Huntington's disease; neurodegenerative disease; gene expression profiling; striatum; transcription
Received June 30, 2008; revised July 31, 2008; accepted Aug. 4, 2008.
Correspondence should be addressed to Ruth Luthi-Carter, Laboratory of Functional Neurogenomics, AI2138 Station 15, Brain Mind Institute, Faculty of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland. Email: ruth.luthi-carter{at}epfl.ch
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