Mutant huntingtin affects the rate of transcription of striatum‐specific isoforms of phosphodiesterase 10A

Abstract

Huntington's disease (HD) is caused by the inheritance of a copy of the gene encoding mutant huntingtin with an expanded CAG repeat. Phosphodiesterase 10A (PDE10A) mRNA decreases in transgenic HD mice expressing exon 1 of the human huntingtin gene (HD). The mouse PDE10A mRNA is expressed through alternative splicing and polyadenylation in a tissue-specific manner and that transcription of striatal PDE10A mRNA is driven by two promoters. PDE10A2 is the predominant isoform of the gene is expressed in the striatum. Using in situ hybridization and quantitative RT-PCR, we determined that decreased steady-state levels of PDE10A2 mRNA were caused by an altered transcription initiation rate rather than by post-transcriptional mRNA instability in HD mice. Transcription from three initiation sites located within a 50-bp region in the PDE10A2-specific promoter was differentially affected by the presence of the mutant huntingtin transgene. The mouse and human PDE10A2 promoters are highly conserved with respect to the relative position of cis-regulatory elements. Several transcription factors that have been shown to interact with mutant huntingtin, including Sp1, neuron restrictive silencing factor, TATA-binding protein and cAMP-response element binding protein, are unlikely to be involved in mutant huntingtin-induced PDE10A2 transcriptional dysregulation.

Striatal Medium Spiny Neurons Terminate in a Distinct Region in the Lateral Hypothalamic Area and Do Not Directly Innervate Orexin/Hypocretin- or Melanin-Concentrating Hormone-Containing Neurons

“…PDE10A2 is a PDE10A splice variant (Hu et al, 2004), which is selectively expressed in striatal MSNs in the mouse brain (Sano et al, 2006(Sano et al, , 2007. Therefore, by knocking in tTA into the PDE10A2 gene locus, selective distribution of tTA in striatal MSNs was achieved in a manner that recapitulates expression of PDE10A2 (Sano et al, 2007).…”

Cyclic Nucleotide Phosphodiesterases: Molecular Regulation to Clinical Use

“…In addition, there is some indirect evidence that PDE10A may be involved in long-term potentiation in the hippocampus as the level of its mRNA has been reported to be elevated after long-term potentiation (O'Connor et al, 2004). PDE10A mRNA and protein levels are decreased in the striatal region of brains from Huntington's diseased transgenic mice and the decrease precedes the onset of symptoms Hu et al, 2004). Thus, it is postulated that loss of PDE10 may cause an alteration in cyclic nucleotide signaling that contributes to the loss of neuronal function produced by the disease.…”

Chronic Suppression of Phosphodiesterase 10A Alters Striatal Expression of Genes Responsible for Neurotransmitter Synthesis, Neurotransmission, and Signaling Pathways Implicated in Huntington's Disease

“…However, the loss of striatally enriched transcripts early in disease or R6/2 model progression could be a consequence of transcriptional dysfunction caused by a direct interaction of soluble huntingtin protein with transcription factors required to direct expression of particular mRNAs or compensation for dysfunctional neuronal signaling. Studies of the regulation of the PDE10A promoter have not revealed any candidate regulatory transcription factors capable of decreasing PDE10A mRNA as observed in the R6/R2 mouse model (Hu et al, 2004). Given that inhibition of PDE10A is a powerful inducer of CREB-mediated transcription in striatum, and the propensity of this circuit to compensate for chronic deficits in signaling cascades, it seems possible that down-regulation of PDE10A early in the disease process may be an adaptive response to compensate for loss of cAMP signaling.…”

“…Transcripts for PDE10A and PDE1B are abundant in striatum, but exhibit significant down-regulation in HD brain and the R6/2 mouse model. The decrease in PDE10A mRNA is caused by decreases in transcriptional initiation of the striatally expressed PDE10A2 gene, which initiates at sites 2 and 3 in the exon 1a-specific promoter (Hu et al, 2004), and loss of the PDE10A enzyme early in disease has been proposed as a contributing factor in progression of disease . However, the loss of striatally enriched transcripts early in disease or R6/2 model progression could be a consequence of transcriptional dysfunction caused by a direct interaction of soluble huntingtin protein with transcription factors required to direct expression of particular mRNAs or compensation for dysfunctional neuronal signaling.…”