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.
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.
authors.affiliation: Laboratory of Functional Neurogenomics, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Switzerland.
authors.forename: Heike
authors.initials: H
authors.lastname: Runne
authors.forename: Etienne
authors.initials: E
authors.lastname: Régulier
authors.forename: Alexandre
authors.initials: A
authors.lastname: Kuhn
authors.forename: Diana
authors.initials: D
authors.lastname: Zala
authors.forename: Ozgun
authors.initials: O
authors.lastname: Gokce
authors.forename: Valérie
authors.initials: V
authors.lastname: Perrin
authors.forename: Beate
authors.initials: B
authors.lastname: Sick
authors.forename: Patrick
authors.initials: P
authors.lastname: Aebischer
authors.forename: Nicole
authors.initials: N
authors.lastname: Déglon
authors.forename: Ruth
authors.initials: R
authors.lastname: Luthi-Carter
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000473:pathology; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004745:Enkephalins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000235:genetics*; D016086:Lentivirus / Q000502:physiology; D046228:Microarray Analysis; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D020710:RGS Proteins / Q000378:metabolism; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D014162:Transfection / Q000379:methods
chemical_list: D004745:Enkephalins; D010455:Peptides; D010750:Phosphoproteins; D011498:Protein Precursors; D020710:RGS Proteins; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C485184:enhanced green fluorescent protein; C029992:proenkephalin; D049452:Green Fluorescent Proteins; C098799:RGS4 protein; C097188:polyglutamine