Publication type: Article in scientific journal
Type of review: Peer review (publication)
Title: 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
Authors: Runne, Heike
Régulier, Etienne
Kuhn, Alexandre
Zala, Diana
Gokce, Ozgun
Perrin, Valérie
Sick, Beate
Aebischer, Patrick
Déglon, Nicole
Luthi-Carter, Ruth
DOI: 10.1523/JNEUROSCI.3044-08.2008
Published in: Journal of Neuroscience
Volume(Issue): 28
Issue: 39
Pages: 9723
Pages to: 9731
Issue Date: 2008
Publisher / Ed. Institution: Society for Neuroscience
ISSN: 1529-2401
0270-6474
Language: English
Subject (DDC): 572: Biochemistry
Abstract: 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 D(1) receptor (DRD1), DRD2, CNR1 (cannabinoid CB(1) 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.
URI: https://digitalcollection.zhaw.ch/handle/11475/14044
Fulltext version: Published version
License (according to publishing contract): Licence according to publishing contract
Departement: School of Engineering
Organisational Unit: Institute of Data Analysis and Process Design (IDP)
Appears in collections:Publikationen School of Engineering

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