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.

The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

“…These mice, and in particular the R6/2 line, have an early onset of symptoms and a fast progression of the disease, showing a life expectancy of approximately 12 to 17 weeks, depending on the colony. The phenotype and neuropathology observed in these mice replicate several features observed in humans, including a progressive motor Luesse et al, 2001;Bolivar et al, 2003Bolivar et al, , 2004 and cognitive impairment Murphy et al, 2000), weight loss, decreased striatal and brain size (Mangiarini et al, 1996), ubiquitinated nuclear and cytoplasmic inclusions of the mutant protein (Davies et al, 1997;Li et al, 1999), altered levels of neurotransmitters (for review see Cha, 2000) and their receptors (Cha et al, 1998), altered gene expression (Luthi-Carter et al, 2000Zucker et al, 2005), diabetes (Hurlbert et al, 1999;Luesse et al, 2001;Andreassen et al, 2002;Björkqvist et al, 2005), which was previously reported in 10-25% of HD patients (Podolsky et al, 1972;Farrer, 1985), as well as several other neuroendocrine changes for review see Petersén and Björkqvist, 2006), and premature death (Mangiarini et al, 1996). Interestingly, both R6/2 (Gil et al, 2004 and R6/1 (Lazic et al, 2004(Lazic et al, , 2006 mice show a specific decrease in hippocampal cell proliferation and neurogenesis, which may account for some of their cognitive deficits (see below).…”

Genetic interaction between expanded murine Hdh alleles and p53 reveal deleterious effects of p53 on Huntington's disease pathogenesis

“…If mutant htt can alter the activity of p53, one would predict that cells expressing mutant htt might have numerous changes in their transcriptional profile. In fact, a number of transcriptional alterations have been identified by gene expression profile, RT-PCR, and Northern blot in response to mutant htt (Li et al, 1999;Cha, 2000;Luthi-Carter et al, 2000;Luthi-Carter et al, 2002;Sipione et al, 2002;Kotliarova et al, 2005;Zucker et al, 2005).…”

Alterations of Interneurons of the Gerbil Hippocampus after Transient Cerebral Ischemia: Effect of Pitavastatin

“…It is known that nNOS is restricted to occasional interneurons in the hippocampus (Dinerman et al, 1994). In the mouse striatum, furthermore, nNOS-positive cells are known to be interneurons (Zucker et al, 2005). However, little is known about the exact changes of nNOS expression as interneurons in the hippocampus after transient cerebral ischemia in gerbils.…”