title: Transcriptional dysregulation in striatal projection- and interneurons in a mouse model of Huntington's disease: neuronal selectivity and potential neuroprotective role of HAP1.
abstract: Transcriptional dysregulation has been described as a central mechanism in the pathogenesis of Huntington's disease (HD), in which medium spiny projection neurons (MSN) selectively degenerate whereas neuronal nitric-oxide-synthase-positive interneurons (nNOS-IN) survive. In order to begin to understand this differential vulnerability we compared mRNA levels of selected genes involved in N-methyl-D-aspartate (NMDA) glutamate receptor and calcium (Ca2+) signaling pathways in MSN and nNOS-IN from 12-week-old R6/2 mice, a transgenic mouse model of HD and wild-type littermates. We undertook a laser capture microdissection (LCM) study to examine the contribution of transcriptional dysregulation in candidate genes involved in these two signaling pathways in discrete populations of striatal neurons. The use of LCM in combination with quantitative real-time polymerase chain reaction (Q-PCR) allowed us to quantify the neuronal abundance of candidate mRNAs. We found different transcriptional alterations in R6/2 neurons for both MSN and nNOS-IN, indicating that global transcriptional dysregulation alone does not account for selective vulnerability. Further, we observed a striking enrichment of several mRNAs in the nNOS-IN population, including that for the NMDA receptor subunit NR2D, the postsynaptic density protein 95 (PSD-95) and the huntingtin-associated protein 1 (HAP1) as well as nitric-oxide-synthase (nNOS) mRNA itself. The higher expression levels of these molecules in nNOS-IN when compared with MSN together with an association of nNOS, NR2D and HAP1 in a protein complex with PSD-95 suggest that these proteins may be involved in protective pathways that contribute to the resistance of this interneuron population to neurodegeneration in HD.
authors.affiliation: Department of Neurology, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital and Harvard Medical School, Boston 02129, USA. birgit.zucker@gmx.de
authors.forename: Birgit
authors.initials: B
authors.lastname: Zucker
authors.forename: Ruth
authors.initials: R
authors.lastname: Luthi-Carter
authors.forename: Jibrin A
authors.initials: JA
authors.lastname: Kama
authors.forename: Anthone W
authors.initials: AW
authors.lastname: Dunah
authors.forename: Edward A
authors.initials: EA
authors.lastname: Stern
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Fox
authors.forename: David G
authors.initials: DG
authors.lastname: Standaert
authors.forename: Anne B
authors.initials: AB
authors.lastname: Young
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Augood
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D051528:Guanylate Kinases; D006816:Huntington Disease / Q000378:metabolism*; D007395:Interneurons / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; C490758:Hap1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C464436:NR2D NMDA receptor; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C033652:postsynaptic density proteins; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D051528:Guanylate Kinases