Transcriptional signatures in Huntington's disease

Jang-Ho, J.

doi:10.1016/j.pneurobio.2007.03.004

Cited by 240 publications

(184 citation statements)

References 176 publications

(178 reference statements)

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“…Transcriptional deregulation has been proposed as an important pathogenic mechanism in HD. 23 The presence of an expanded polyglutamine domain in the protein can disrupt transcription through several mechanisms such as interaction or sequestration of transcription factors. 28 For instance, it has been recently shown in vitro, and in the striatum and cortex of R6/2 mice that NF-Y is one of the transcription factors sequestered by mhtt.…”

Section: Discussionmentioning

confidence: 99%

“…20 Recently, it has been shown that PHLPP1 participates in the regulation of MAPK signaling required for some forms of hippocampus-dependent memory, 21 and that changes in total PHLPP1 protein levels are important in regulating the degree of Akt phosphorylation at Ser473 in the hippocampus. 22 Because the presence of mhtt can result in alteration of gene expression, 23 in the present work we sought to determine whether mhtt could induce changes in PHLPP1 protein levels contributing to maintain high levels of pAkt (Ser473) in transgenic mouse models and in the brain of HD patients.…”

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confidence: 99%

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PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3K/Akt pro-survival pathway in Huntington's disease striatum

et al. 2009

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Dysregulation of gene expression is one of the mechanisms involved in the pathophysiology of Huntington's disease (HD). Here, we examined whether mutant huntingtin regulates the levels of PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1), a phosphatase that specifically dephosphorylates Akt at Ser473. Our results show decreased PHLPP1 protein levels in knock-in models (Hdh Q111/Q111 mouse striatum and STHdh Q111/Q111 cells), in the striatum of N-terminal exon-1 mutant huntingtin transgenic mouse models (R6/1; R6/1 : BDNF þ /À, R6/2 and Tet/HD94) and in the putamen of HD patients. Quantitative PCR analysis revealed a reduction in PHLPP1 mRNA levels in the striatum of R6/1 compared with wild-type mice. Coincident with reduced PHLPP1 protein levels, we observed increased phosphorylated Akt (Ser473) levels specifically in the striatum. The analysis of the conditional mouse model Tet/HD94 disclosed that after mutant huntingtin shutdown PHLPP1 levels returned to wild-type levels whereas phospho-Akt levels were partially reduced. In conclusion, our results show that mutant huntingtin downregulates PHLPP1 expression. In the striatum, these reduced levels of PHLPP1 can contribute to maintain high levels of activated Akt that may delay cell death and allow the recovery of neuronal viability after mutant huntingtin silencing.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3K/Akt pro-survival pathway in Huntington's disease striatum

et al. 2009

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“…Thus altered miRNA expressions in HD may change expressions of hundreds of genes, which in turn may provide explanation at least to some proportions, of altered gene expressions observed in HD. 13 Altered miRNAs by changing expression of their target genes, may also participate in diverse cellular dysfunctions observed in HD. 14 Few miRNAs have been shown to target genes that are causal for neurodegenerative diseases.…”

Section: O N O T D I S T R I B U T Ementioning

confidence: 99%

Micro RNA -214,-150,-146a and-125b targetHuntingtingene

Sinha¹,

Ghose²,

Bhattarcharyya³

2011

RNA Biology

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“…Transcriptional repression of key neuronal transcripts, including neurotransmitters, growth factors, and their cognate receptors, is consistently observed and implicated in disease pathogenesis. Among the critical genes whose expression is repressed in HD mouse models and human brain tissue are the dopamine receptor 2 (Drd2), preproenkephalin (Penk1), the cannabinoid receptor (Cb2), and brain-derived neurotrophic factor (Bdnf) (4,5).…”

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confidence: 99%

Targeting H3K4 trimethylation in Huntington disease

Vashishtha

Ng²,

Yildirim³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

153

173

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Transcriptional dysregulation is an early feature of Huntington disease (HD). We observed gene-specific changes in histone H3 lysine 4 trimethylation (H3K4me3) at transcriptionally repressed promoters in R6/2 mouse and human HD brain. Genome-wide analysis showed a chromatin signature for this mark. Reducing the levels of the H3K4 demethylase SMCX/Jarid1c in primary neurons reversed down-regulation of key neuronal genes caused by mutant Huntingtin expression. Finally, reduction of SMCX/Jarid1c in primary neurons from BACHD mice or the single Jarid1 in a Drosophila HD model was protective. Therefore, targeting this epigenetic signature may be an effective strategy to ameliorate the consequences of HD.polyglutamine | neurodegeneration H untington disease (HD), a neurodegenerative disease (1, 2) characterized by cognitive dysfunction, psychiatric symptoms, and choreic movements (2), exhibits brain region-specific neuronal degeneration in the striatum and cortex. Currently, no disease-modifying treatment is available. The genetic basis of HD is the expansion of an in-frame CAG repeat sequence encoding polyglutamine. Progressive transcriptional dysregulation in both cortex and striatum and atrophy of the cortex are characteristic features (3). Transcriptional repression of key neuronal transcripts, including neurotransmitters, growth factors, and their cognate receptors, is consistently observed and implicated in disease pathogenesis. Among the critical genes whose expression is repressed in HD mouse models and human brain tissue are the dopamine receptor 2 (Drd2), preproenkephalin (Penk1), the cannabinoid receptor (Cb2), and brain-derived neurotrophic factor (Bdnf) (4, 5).We hypothesized that a central event in the pathological program underlying transcriptional dysregulation includes alterations in chromatin structure in the regulatory regions of genes down-regulated in HD. To evaluate this hypothesis, we focused on H3K4 trimethylation (H3K4me3), a mark of transcription start sites (TSSs) and active chromatin (6-8). Growing evidence suggests that this mark is plastic and modulated in conditions of chronic stress, developmental disorders, psychiatric disorders (9-11) as well as during long-term memory consolidation from contextual fear conditioning (12), suggesting a critical function in brain.We first investigated H3K4me3 in the R6/2 mouse model of HD, which shows patterns of transcriptional dysregulation similar to postmortem HD brain (13,14). Using chromatin immunoprecipitation (ChIP), we examined H3K4me3 levels for Bdnf, which is expressed in the cortex, provides trophic support for GABAergic medium spiny neurons, and is expressed at lower levels in HD (5, 15). The potential significance of Bdnf in HD is reflected by transcriptional profiling (16) and therapeutic preclinical studies (17,18). Because H3K4me3 levels were lowered at Bdnf and other promoters in R6/2 mice and key neuronal genes in human HD brain cortex and striata, we expanded our approach to investigate the genome-wide relationship between H3K4me3 an...

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Transcriptional signatures in Huntington's disease

Cited by 240 publications

References 176 publications

PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3K/Akt pro-survival pathway in Huntington's disease striatum

PH domain leucine-rich repeat protein phosphatase 1 contributes to maintain the activation of the PI3K/Akt pro-survival pathway in Huntington's disease striatum

Micro RNA -214,-150,-146a and-125b targetHuntingtingene

Targeting H3K4 trimethylation in Huntington disease

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