Astrocyte-neuron contributions to Huntington’s disease dissected with ZFPs
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE189647 | GEO | 2022/12/15
REPOSITORIES: GEO
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Project description:We used cell-specific zinc finger protein (ZFP) transcriptional repressors to lower mHTT and experimentally evaluated the consequences of neuronal and astrocytic mHTT lowering on HD pathophysiology using cell-type specific RNA-seq
2022-12-15 | GSE211891 | GEO
Project description:Huntington’s disease (HD) is caused by expanded CAG repeats in the Huntingtin gene (HTT) that results in expression of mutant HTT proteins (mHTT) with extended polyglutamine tracts in diverse cells of the body, including striatal neurons and astrocytes. The relative contributions of neurons and astrocytes to disease pathogenesis are unknown for HD and other neurodegenerative diseases. This is a critical issue to address since it has been proposed that neuronal loss in HD and other major neurodegenerative diseases is downstream of astrocytic dysfunction that drives neuronal death. Moreover, astrocyte-to-neuron conversion is considered a promising approach in HD and other neurodegenerative diseases with little reported detriment with regards to normal astrocytic physiological functions, which are varied and extensive in health and disease. Thus, astrocytes are considered both causative and also largely replaceable in neurodegeneration, and their basic contributions to disease pathophysiology relative to neurons remain undefined in vivo. We used genetically encoded and cell-specific zinc finger protein (ZFP) transcriptional repressors to lower mHTT and molecularly dissected neuronal and astrocytic influences on HD pathophysiology at molecular, cellular, and behavioral levels. We found that the major disease drivers were in fact neurons, with astrocytes displaying lesser loss of essential functions such as cholesterol metabolism that were downstream of greater neuronal dysfunction, which encompassed neuromodulation, synaptic, and intracellular signaling. We thus dissected the cell autonomous and non-cell autonomous mechanistic and causal contributions of both neurons and astrocytes to a complex neurodegenerative disease in vivo with wider implications for rescue and repair strategies.
2022-12-15 | PXD030021 | Pride
Project description:Huntington neurodegenerative disease (HD) is associated with extensive down-regulation of neuronal genes. We show preferential down-regulation of super-enhancer-regulated neuronal function genes in the striatum of HD mice. Striatal super-enhancers display extensive H3K27 acetylation within gene bodies and drive transcription characterized by low levels of paused RNAPII. Down-regulation of gene expression is associated with diminished H3K27 acetylation and RNAPII recruitment. Striatal super-enhancers are enriched in binding motifs for Gata transcription factors, such as Gata2 regulating striatal identity genes. Thus, enhancer topography and transcription dynamics are major parameters determining the propensity of a gene to be deregulated in a neurodegenerative disease. RNA profiles in Striatum of WT and R6/1 mice by deep sequencing using Illumina HiSeq 2000.
2015-04-01 | E-GEOD-59571 | biostudies-arrayexpress
Project description:Huntington’s disease (HD) is a chronic neurodegenerative disorder characterized by a late clinical onset despite ubiquitous expression of the mutant Huntingtin gene (HTT) from birth. Transcriptional dysregulation is a pivotal feature of HD. Yet, the genes that are altered in the prodromal period and their regulators, which present opportunities for therapeutic intervention, remain to be elucidated. Using transcriptional and chromatin profiling, we found aberrant transcription and changes in histone H3K27 acetylation in the striatum of R6/1 mice during the presymptomatic disease stages. Integrating these data, we identified the Elk-1 transcription factor as a candidate regulator of prodromal changes in HD. Exogenous expression of Elk-1 exerted beneficial effects in a primary striatal cell culture model of HD, and adeno-associated virus-mediated Elk-1 overexpression alleviated transcriptional dysregulation in R6/1 mice. Collectively, our work demonstrates that aberrant gene expression precedes overt disease onset in HD, identifies the Elk-1 transcription factor as a key regulator linked to early epigenetic and transcriptional changes in HD, and presents evidence for Elk-1 as a target for alleviating molecular pathology in HD.
2019-11-19 | GSE140117 | GEO
Project description:Huntington’s disease (HD) is a chronic neurodegenerative disorder characterized by a late clinical onset despite ubiquitous expression of the mutant Huntingtin gene (HTT) from birth. Transcriptional dysregulation is a pivotal feature of HD. Yet, the genes that are altered in the prodromal period and their regulators, which present opportunities for therapeutic intervention, remain to be elucidated. Using transcriptional and chromatin profiling, we found aberrant transcription and changes in histone H3K27 acetylation in the striatum of R6/1 mice during the presymptomatic disease stages. Integrating these data, we identified the Elk-1 transcription factor as a candidate regulator of prodromal changes in HD. Exogenous expression of Elk-1 exerted beneficial effects in a primary striatal cell culture model of HD, and adeno-associated virus-mediated Elk-1 overexpression alleviated transcriptional dysregulation in R6/1 mice. Collectively, our work demonstrates that aberrant gene expression precedes overt disease onset in HD, identifies the Elk-1 transcription factor as a key regulator linked to early epigenetic and transcriptional changes in HD, and presents evidence for Elk-1 as a target for alleviating molecular pathology in HD.
2019-11-19 | GSE139847 | GEO
Project description:Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease characterized by a late clinical onset of psychiatric, cognitive, and motor symptoms. Transcriptional dysregulation is an early and central disease mechanism which is accompanied by epigenetic alterations in HD. Previous studies demonstrated that targeting transcriptional changes by inhibition of histone deacetylases (HDACs), especially the class I HDACs, provides therapeutic effects. Yet, their exact mechanisms of action and the features of HD pathology, on which these inhibitors act remain to be elucidated. Here, using transcriptional profiling, we found that selective inhibition of HDAC1 and HDAC3 by RGFP109 alleviated transcriptional dysregulation of a number of genes, including the transcription factor genes Neurod2 and Nr4a2, and gene sets and programs, especially those that are associated to insulin-like growth factor pathway, in the striatum of R6/1 mice. RGFP109 treatment led to a modest improvement of the motor skill learning and coordination deficit on the RotaRod test, while it did not alter the locomotor and anxiety-like phenotypes in R6/1 animals. We also found, by volumetric MRI, a widespread brain atrophy in the R6/1 mice at the symptomatic disease stage, on which RGFP109 showed no significant effects. Collectively, our combined work suggests that specific HDAC1 and HDAC3 inhibition may offer benefits for alleviating the motor phenotypic deficits and transcriptional dysregulation in HD.
2021-02-04 | GSE160967 | GEO
Project description:Huntington’s disease is a fatal autosomal dominant neurodegenerative disorder, characterized by neuronal cell loss, primarily in the striatum, cortex, and hippocampus, causing motor, cognitive, and psychiatric impairments. Unfortunately, no treatments are yet available to modify the progression of the disease. Recent evidence from Huntington’s disease mouse models suggests that protein phosphorylation (catalysed by kinases and hydrolysed by phosphatases) might be dysregulated, making this major posttranslational modification a potential area of interest to find novel therapeutic targets. Furthermore, environmental enrichment (EE), used to model an active lifestyle in preclinical models, has been shown to alleviate Huntington’s disease-related motor and cognitive symptoms. However, the molecular mechanisms leading to these therapeutic effects are still largely unknown. In this study, we applied a phosphoproteomics approach combined with proteomic analyses on brain samples from pre-motor symptomatic R6/1 Huntington’s disease male mice (HD mice) and their wild-type (WT) littermates, after being housed either in EE conditions, or in standard housing (SH) conditions from 4 to 8 weeks of age (n=6 per group). We hypothesised that protein phosphorylation dysregulations occur prior to motor onset in this mouse model, in two highly affected brain regions, the striatum and hippocampus. Furthermore, we hypothesised that these phosphoproteome alterations are rescued by EE. When comparing 8-week-old HD mice and WT mice in SH conditions, our analysis revealed 229 differentially phosphorylated peptides in the striatum, compared to only 15 differentially phosphorylated peptides in the hippocampus (statistical thresholds FDR0.05, FC1.5). At the same disease stage, minor differences were found in protein expression, with 24 and 22 proteins dysregulated in the striatum and hippocampus, respectively. Notably, we found no differences in striatal protein phosphorylation and protein expression when comparing HD mice and their WT littermates in EE conditions. In the hippocampus, only four peptides were differentially phosphorylated between the two genotypes under EE conditions, and 22 proteins were differentially expressed. Together, our data indicates that protein phosphorylation dysregulations occur in the striatum of HD mice, prior to motor symptoms, and that the kinases and phosphatases leading to these changes in protein phosphorylation might be viable drug targets to consider for this disorder. Furthermore, we show that an early environmental intervention was able to rescue the changes observed in protein expression and phosphorylation in the striatum of HD mice and might underlie the beneficial effects of EE, thus identifying novel therapeutic targets.
2023-03-11 | PXD032205 | Pride
Project description:Gene expression profiling of striatum in R6/2 Huntington’s disease (HD) model mouse. Striatum gene set contained gene expression alterations in other neuronal populations, such as oligodendrocyte, astrocyte, microglia and interneuron.
2020-06-03 | GSE113929 | GEO
Project description:Huntington disease (HD) is a fatal neurodegenerative disorder without cure, caused by an aberrant expansion of CAG repeats in the exon 1 of the Huntingtin (HTT) gene. Although the negative correlation between the number of CAG repeats and the age of disease onset is well established, additional factors may contribute to the high heterogeneity in the complex manifestation of the symptoms among patients. This variability is also observed in the phenotype of mouse models, even under controlled genetic and environmental conditions. To better understand this phenomenon, we analyzed the R6/1 strain in search of potential correlates between pathological motor/cognitive phenotypical traits and transcriptional alterations. HD-related genes (e.g., Penk, Plk5, Itpka), despite being downregulated across the examined brain areas (prefrontal cortex, striatum, hippocampus and cerebellum), exhibited a tissue-specific correlative association with particular phenotypical traits, attributable to the contribution of the brain region to regulate the trait (e.g., striatum and rotarod performance, cerebellum and feet clasping). Focusing on the striatum, we determined that the transcriptional dysregulation associated with HD was partially exacerbated in those mice showing poor phenotypical scores, affecting genes extensively described in this disease (e.g. Pde10a, Drd1, Drd2, Ppp1r1b). However, we also observed transcripts associated with relative better outcome, such as CCAAT-binding transcription factor NF-Y and others related with neuronal development, apoptosis and differentiation. In this study we demonstrate that altered brain transcription is capable of tracking the variations in the manifestation of HD-like symptoms in mouse models that may be extrapolated to the highly heterogeneous population of HD patients.
2019-12-29 | GSE135057 | GEO
Project description:Deregulated intracellular Ca2+ homeostasis underlies synaptic dysfunction and is a common feature in neurodegenerative processes, including Huntington's disease (HD). DREAM/calsenilin/KChIP-3 is a multifunctional Ca2+ binding protein that controls the expression level and/or the activity of several proteins related to Ca2+ homeostasis, neuronal excitability and neuronal survival. We found that expression of endogenous DREAM (DRE antagonist modulator) is reduced in the striatum of R6 mice, in STHdh-Q111/111 knock in striatal neurons and in HD patients. DREAM down regulation in R6 striatum occurs early after birth, well before the onset of motor coordination impairment, and could be part of an endogenous mechanism of neuroprotection, since i) R6/2 mice hemizygous for the DREAM gene (R6/2xDREAM+/-) showed delayed onset of locomotor impairment and prolonged lifespan, ii) motor impairment after chronic administration of 3-NPA was reduced in DREAM knockout mice and enhanced in daDREAM transgenic mice and, iii) lentiviral-mediated DREAM expression in STHdh-Q111/111 knock in cells sensitizes them to oxidative stress. Transcriptomic analysis showed that changes in gene expression in R6/2 striatum were notably reduced in R6/2xDREAM+/- striatum. Chronic administration of repaglinide, a molecule able to bind to DREAM in vitro and to accelerate its clearance in vivo, delayed the onset of motor dysfunction, reduced striatal loss and prolonged the lifespan in R6/2 mice. Furthermore, exposure to repaglinide protected STHdh-Q111/111 knock in striatal neurons sensitized to oxidative stress by lentiviral-mediated DREAM overexpression. Thus, genetic and pharmacological evidences disclose a role for DREAM silencing in early neuroprotective mechanisms in HD.
2016-02-01 | GSE48104 | GEO