Decreased cAMP Response Element-mediated Transcription

Abstract

Huntington's disease (HD) is one of nine neurodegenerative diseases caused by an expanded polyglutamine (polyQ) tract within the disease protein. To characterize pathways induced early in HD, we have developed stable inducible PC12 cell lines expressing wild-type or mutant forms of huntingtin exon 1 fragments or the full-length huntingtin protein. Three cAMP response element-binding protein (CREB)-binding protein-dependent transcriptional pathways, regulated by cAMP response element (CRE), retinoic acid response element, and nuclear factor B, show abnormalities in our exon 1 cell model. Of these, the CRE pathway shows the earliest disruption and is significantly down-regulated as early as 12 h following mutant htt transgene induction. This pathway is also the only one of the three that is similarly perturbed in our full-length HD model, where it is also down-regulated at an early time point, compatible with observations in HD brains. Reduced CRE-dependent transcription may contribute to polyQ disease pathogenesis because overexpression of transcriptionally active CREB, but not an inactive form of the protein, is able to protect against polyQ-induced cell death and reduce aggregation.Huntington's disease (HD) 1 is a devastating, autosomal dominant, neurodegenerative disorder caused by a CAG trinucleotide repeat expansion within exon 1 of the huntingtin (htt) gene (1). HD is associated with expansions in excess of 35 CAG repeats, which are translated into an abnormally long glutamine tract (polyQ) within htt. This is believed to confer a deleterious gain-of-function onto the protein (2). HD belongs to a family of nine neurodegenerative diseases caused by polyQ expansions, including spinocerebellar ataxia types 1, 2, 3, 6, 7, and 17; spinobulbar muscular atrophy; and dentatorubral pallidoluysian atrophy.PolyQ diseases are characterized by progressive neuronal loss and by the formation of intraneuronal protein aggregates containing the mutant proteins (reviewed in Ref. 3). Although the precise roles of these aggregates in the disease process are still under debate, recent findings have shown them to have a possible pathogenic role in vivo (4). Normally, htt is distributed predominantly within the cytoplasm, although some fulllength htt and N-terminal cleavage fragments are also found in the nucleus (5, 6). For mutant htt, however, nuclear localization is increased, suggesting that transcriptional disruption may be a possible mechanism for polyQ disease pathogenesis (reviewed in Ref. 7).Soluble and aggregated polyQ proteins have been shown to interact/associate with a number of transcription factors and co-factors, which in several cases results in their functional impairment (reviewed in Ref. 7). To date, most attention has fallen on disruption of the transcriptional co-activator protein cAMP response element-binding protein (CBP). CBP facilitates gene transcription under normal conditions by acting as a bridge between specific upstream transcription factors and the basal transcriptional machinery (reviewed in Refs....

Transcriptional dysregulation in Huntington's disease: a failure of adaptive transcriptional homeostasis

“…The expression of CREB target genes has been reported to be downregulated in both in vitro as well as in vivo models of HD [16, 24]. The expression of one of these CREB target genes [peroxisome proliferator-activated receptor (PPAR) gamma coactivator (PGC)-1α], which has a crucial role in mitochondrial biogenesis, is reduced in HD mice as well as postmortem brains of patients with HD [25, 26].…”

Efficacy of Selective PDE4D Negative Allosteric Modulators in the Object Retrieval Task in Female Cynomolgus Monkeys (Macaca fascicularis)

“…HD is caused exclusively by mutations in the huntingtin ( HTT ) gene. Although the exact nature of the interaction between huntingtin (HTT) protein and cyclic nucleotide signalling components is unclear, several reports point to dysregulation of cAMP pathways as a contributor to disease pathogenesis [21]–[30]. Loss of function of the transcriptional modulator CREB binding protein (CBP) has been postulated to contribute to the loss of neuronal function, as well as to the overall strong transcriptional deficits associated with HD, potentially through direct binding to HTT [21], [28], [31], [32].…”

cAMP-response element-binding protein and heat-shock protein 70 additively suppress polyglutamine-mediated toxicity inDrosophila

“…Many genes regulated by the cAMP signaling pathway are down-regulated at an early symptomatic stage in cellular and mouse models of Huntington's disease (12,14). Forskolin stimulation of adenylyl cyclase, as well as overexpression of an activated CREB, ameliorated mutant Huntingtin-(htt) induced phenotypes in a cell culture model (7,12). Knocking out CREB leads to apoptosis and neurodegeneration in sensory neurons of genetically modified mice (15).…”