Analysis of differentially expressed genes between Huntington’s disease and control iPSCs derived GABA MS-like neurons
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE77558 | GEO | 2016/02/04
SECONDARY ACCESSION(S): PRJNA310786
REPOSITORIES: GEO
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Project description:Somatic expansion of the Huntington’s disease (HD) CAG repeat drives the rate of a pathogenic process resulting in neuronal cell death. Although mechanisms of neuronal toxicity are not well delineated, transcriptional dysregulation is a likely contributor. Chromatin modifiers are implicated in both mechanisms of CAG instability and transcriptional dysregulation. Here, we tested whether histone deacetylase genes Hdac2 and Hdac3 modify molecular and cellular phenotypes in HttQ111 knock-in mice using conditional knockouts in striatal medium-spiny striatal neurons (MSNs) exhibiting extensive CAG expansion and exquisite disease vulnerability. MSN-specific Hdac2 or Hdac3 knockout attenuated CAG expansion, with the Hdac2 knockout impacting nuclear huntingtin pathology. Hdac2 knockout resulted in a substantial transcriptional response that included reversal of transcriptional dysregulation elicited by the HttQ111 allele. Our results identify novel modifiers of CAG expansion in MSNs, providing testable mechanistic hypotheses, and a potentially complex relationship between Htt and Hdac2 with implications for targeting transcriptional dysregulation in HD.
2020-06-01 | GSE148440 | GEO
Project description:Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the huntingtin gene (HTT), which codes for the pathologic mutant HTT (mHTT) protein. Since normal HTT is thought to be important for brain function, we engineered zinc finger protein transcription factors (ZFP-TFs) to target the pathogenic CAG repeat and selectively lower mHTT as a therapeutic strategy. Using patient-derived fibroblasts and neurons, we demonstrate that ZFP-TFs selectively repress >99% of HD-causing alleles over a wide dose range, while preserving expression of >86% of normal alleles. Other CAG-containing genes are minimally affected, and virally delivered ZFP-TFs are active and well tolerated in HD neurons beyond 100 days in culture and at least 9 months in the mouse brain. Using three HD mouse models, we demonstrate improvements in a range of molecular, histopathological, electrophysiological, and functional endpoints. Our findings support the continued development of an allele-selective ZFP-TF for the treatment of HD.
2019-06-30 | GSE127821 | GEO
Project description:Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the huntingtin gene (HTT), which codes for the pathologic mutant HTT (mHTT) protein. Since normal HTT is thought to be important for brain function, we engineered zinc finger protein transcription factors (ZFP-TFs) to target the pathogenic CAG repeat and selectively lower mHTT as a therapeutic strategy. Using patient-derived fibroblasts and neurons, we demonstrate that ZFP-TFs selectively repress >99% of HD-causing alleles over a wide dose range, while preserving expression of >86% of normal alleles. Other CAG-containing genes are minimally affected, and virally delivered ZFP-TFs are active and well tolerated in HD neurons beyond 100 days in culture and at least 9 months in the mouse brain. Using three HD mouse models, we demonstrate improvements in a range of molecular, histopathological, electrophysiological, and functional endpoints. Our findings support the continued development of an allele-selective ZFP-TF for the treatment of HD.
2019-06-30 | GSE127820 | GEO
Project description:Huntington’s disease (HD) is a devastating disease for which currently no therapy is available. It is a progressive autosomal dominant neurodegenerative disorder that is caused by a CAG repeat expansion in the HD gene, resulting in an expansion of polyglutamines at the N-terminal end of the encoded protein, designated huntingtin, and the accumulation of cytoplasmic and nuclear aggregates. Not only is there a loss of normal huntingtin function, upon expansion of the CAG repeat there is also a gain of toxic function of the huntingtin protein and this affects a wide range of cellular processes. To identify groups of genes that could play a role in the pathology of Huntington’s disease, we studied mRNA changes in an inducible PC12 model of Huntington’s disease before and after aggregates became visible. This is the first study to show the involvement Nrf2-responsive genes in the oxidative stress response in HD. Oxidative stress related transcripts were altered in expression suggesting a protective response in cells expressing mutant huntingtin at an early stage of cellular pathology. Furthermore, there was a down-regulation of catecholamine biosynthesis resulting in lower dopamine levels in culture. Our results further demonstrate an early impairment of transcription, the cytoskeleton, ion channels and receptors. Given the pathogenic impact of oxidative stress and neuroinflammation, the Nrf2-ARE signaling pathway is an attractive therapeutic target for neurodegenerative diseases. Keywords: Gene expression analysis, Huntington's disease, oxidative stress, PC12 cell model
2008-09-29 | GSE10581 | GEO
Project description:Recent data strongly suggest HTT CAG repeat expansion drives Huntington’s disease (HD) pathogenesis and that disease development is modulated by components of the DNA damage response (DDR) pathway. FAN1 has been identified as a major HD modifier which slows expansion of the HTT CAG repeat in several cell and animal HD models. Here we show dual FAN1 activities act to inhibit repeat expansion. A highly conserved SPYF motif in the FAN1 N-terminus is required for an MLH1 interaction, which slows expansion, with FAN1 nuclease activity also contributing towards repeat stabilisation. Our data supports a model where FAN1 binds MLH1, restricting its recruitment by MSH3 and the formation of the functional DNA mismatch repair (MMR) complex believed to promote CAG repeat expansion. FAN1 nuclease activity functions either concurrently or following MMR activity to maintain repeat stability. These data highlight a potential avenue for HD therapeutics in attenuating somatic expansion.
2022-02-16 | PXD023221 | Pride
Project description:Huntington's Disease (HD) is caused by a CAG expansion in the huntingtin gene. Expansion of the polyglutamine tract in the huntingtin protein results in massive cell death in the striatum of HD patients. We report that human induced pluripotent stem cells (iPSCs) derived from HD patient fibroblasts can be corrected by replacing the expanded CAG repeat with a normal repeat using homologous recombination, and that the correction persists in iPSC differentiation into DARPP-32 positive neurons in vitro and vivo. Further, correction of the HD-iPSCs normalized pathogenic HD signaling pathways (cadherin, TGF-?, BNDF, caspase activation), and reversed disease phenotypes such as susceptibility to cell death and altered mitochondrial bioenergetics in neural stem cells. The ability to make patient-specific, genetically corrected iPSCs from HD patients will provide relevant disease models in identical genetic backgrounds and is a critical step for the eventual use of these cells in cell replacement therapy. 16 experimental samples were used overall. There were 8 replicates per group, with one group being the control, and the other being the experimental. Comparison was carried out on the Nimblegen platform.
2012-06-14 | E-GEOD-37547 | biostudies-arrayexpress
Project description:In Huntington’s disease (HD), expanded HTT CAG repeat length correlates strongly with age at motor onset, indicating that it determines the rate of the disease process leading to diagnostic clinical manifestations. Similarly, in normal individuals, HTT CAG repeat length is correlated with biochemical differences that reveal it as a functional polymorphism. Here, we tested the hypothesis that gene expression signatures can capture continuous, length-dependent effects of the HTT CAG repeat. Using gene expression datasets for 107 HD and control lymphoblastoid cell lines, we constructed mathematical models in an iterative manner, based upon CAG correlated gene expression patterns in randomly chosen training samples, and tested their predictive power in test samples. Predicted CAG repeat lengths were significantly correlated with experimentally determined CAG repeat lengths, whereas models based upon randomly permuted CAGs were not at all predictive. Predictions from different batches of mRNA for the same cell lines were significantly correlated, implying that CAG length-correlated gene expression is reproducible. Notably, HTT expression was not itself correlated with HTT CAG repeat length. Taken together, these findings confirm the concept of a gene expression signature representing the continuous effect of HTT CAG length and not primarily dependent on the level of huntingtin expression. Such global and unbiased approaches, applied to additional cell types and tissues, may facilitate the discovery of therapies for HD by providing a comprehensive view of molecular changes triggered by HTT CAG repeat length for use in screening for and testing compounds that reverse effects of the HTT CAG expansion. To evaluate the continuous analytical approach as a strategy to discover the molecular consequences of the HTT CAG repeat, genome-wide gene expression datasets were generated from a panel of 107 human lymphoblastoid cell lines with HTT CAGs spanning the entire spectrum of allele sizes.
2013-05-03 | E-GEOD-34721 | biostudies-arrayexpress
Project description:Huntington's Disease (HD) is caused by a CAG expansion in the huntingtin gene. Expansion of the polyglutamine tract in the huntingtin protein results in massive cell death in the striatum of HD patients. We report that human induced pluripotent stem cells (iPSCs) derived from HD patient fibroblasts can be corrected by replacing the expanded CAG repeat with a normal repeat using homologous recombination, and that the correction persists in iPSC differentiation into DARPP-32 positive neurons in vitro and vivo. Further, correction of the HD-iPSCs normalized pathogenic HD signaling pathways (cadherin, TGF-β, BNDF, caspase activation), and reversed disease phenotypes such as susceptibility to cell death and altered mitochondrial bioenergetics in neural stem cells. The ability to make patient-specific, genetically corrected iPSCs from HD patients will provide relevant disease models in identical genetic backgrounds and is a critical step for the eventual use of these cells in cell replacement therapy.
2012-06-15 | GSE37547 | GEO
Project description:The amplification of a CAG repeat in the gene coding for huntingtin (HTT) leads to Huntington’s disease (HD). At the protein level, this translates into the expansion of a poly-glutamine (polyQ) stretch in the HTT N-terminus, which renders HTT aggregation-prone by unknown mechanisms. Here we investigate the effects of polyQ expansion on the HTT-HAP40 complex, where HTT structure is substantially stabilized. Surprisingly, our biophysical, cryo-EM and crosslinking mass spectrometry experiments reveal no major changes between 17QHTT-HAP40 (wild type), 46QHTT-HAP40 (typical polyQ length in HD patients) and 128QHTT-HAP40 (extreme polyQ length). Thus, the proposed destabilizing effect of HTT polyQ expansion may not suffice to alter the HTT-HAP40 complex, suggesting that polyQ expansion does not have a major global effect on HTT structure.
2021-03-19 | PXD018451 | Pride
Project description:Huntington’s disease (HD), caused by a CAG repeat expansion in the huntingtin (HTT) gene, is characterized by abnormal protein aggregates and motor and cognitive dysfunction. Htt protein is ubiquitously expressed, but the striatal medium spiny neuron (MSN) is most susceptible to neuronal dysfunction and death. Abnormal gene expression represents a core pathogenic feature of HD, but the relative roles of cell-autonomous and non-cell-autonomous effects on transcription remain unclear. To determine the extent of cell-autonomous dysregulation in the striatum in vivo, we examined genome-wide RNA expression in symptomatic D9-N171-98Q (a.k.a. DE5) transgenic mice in which the forebrain expression of the first 171 amino acids of human Htt with a 98Q repeat expansion is limited to MSNs. Microarray data generated from these mice were compared to those generated on the identical array platform from a pan-neuronal HD mouse model, R6/2, carrying two different CAG repeat lengths, and a relatively high degree of overlap of changes in gene expression was revealed. We further focused on known canonical pathways associated with excitotoxicity, oxidative stress, mitochondrial dysfunction, dopamine signaling and trophic support, among others. While genes related to excitotoxicity, dopamine signaling and trophic support, were altered in both DE5 and R6/2 transgenic mice, which may be either cell-autonomous or non-cell-autonomous,, genes related to mitochondrial dysfunction, oxidative stress and the peroxisome proliferator-activated receptor are primarily affected in DE5 transgenic mice, indicating cell autonomous mechanisms Overall, our results demonstrate that HD-induced dysregulation of the striatal transcriptome can be largely attributed to intrinsic effects of mutant Htt,,such that mutant Htt-induced effects in cortical neurons is not necessary for striatal dysfunction/degeneration. Striatum from DE5 transgenic mice vs. wt littermate controls
2011-01-01 | E-GEOD-25232 | biostudies-arrayexpress