Transcriptional dysregulation in striatal projection- and interneurons in a mouse model of Huntington's disease: Neuronal selectivity and potential neuroprotective role of HAP1

Birgit Zucker, Ruth Luthi-Carter, Jibrin A. Kama, Anthone W. Dunah, Edward A. Stern, Jonathan H. Fox, David G. Standaert, Anne B. Young, Sarah J. Augood

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92 Scopus citations

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.

Original languageEnglish
Pages (from-to)179-189
Number of pages11
JournalHuman Molecular Genetics
Volume14
Issue number2
DOIs
StatePublished - 15 Jan 2005
Externally publishedYes

Bibliographical note

Funding Information:
The authors wish to thank Lianna R. Orlando, Ippolita Cantuti-Castelvetri, Kimberly B. Kegel, Jang-Ho J. Cha, Penelope J. Hallett, Zane Hollingsworth and Christine Keller-McGandy for very helpful discussions, Morgan Sheng for the kind gift of the NR2B antibody. This study was supported by the Hereditary Disease Foundation, the Deutsche For-schungsgemeinschaft (ZU 125/1-1 to B.Z.), NIH Grant NS045896 (to S.J.A.) and United States Public Health Service Grant AG13617 (to A.B.Y.).

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