Modeling endogenous HTT/mHTT pathogenesis in fibroblasts and striatal GABAergic neurons from a Mongolian family with Huntington’s disease
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PROVIDER: PRJNA763815 | ENA |
REPOSITORIES: ENA
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Project description:Transcriptional dysregulation in Huntington’s disease (HD) causes functional deficits in striatal neurons. Here, we performed Patch-seq in an in vitro HD model to investigate the effects of mutant huntingtin (Htt) on synaptic transmission and gene transcription in single striatal neurons. We found that expression of mutant Htt decreased the synaptic output of striatal neurons in a cell autonomous fashion and identified a number of genes, whose dysregulation was correlated with physiological deficiencies in mutant Htt neurons. In support of a pivotal role for epigenetic mechanisms in HD pathophysiology, we found that inhibiting histone deacetylase 1/3 activities rectified several functional and morphological deficits and alleviated the aberrant transcriptional profiles in mutant Htt neurons. With this study, we demonstrate that Patch-seq technology can be applied both to better understand molecular mechanisms underlying a complex neurological disease at single-cell level and to provide a platform for screening for therapeutics for the disease.
2021-05-05 | GSE171099 | GEO
Project description:Progressive striatal gene expression changes and epigenetic alterations are a prominent feature of Huntington’s disease (HD), but direct relationships between the huntingtin (HTT) protein and chromatin remain poorly described. Here, using chromatin immunoprecipitation and sequencing (ChIP-seq), we show that HTT reproducibly occupies specific locations in the mouse genome, including thousands of genomic loci that are differentially occupied in striatal tissue from a knock-in mouse model of the HD mutation (B6.HttQ111/+) versus wildtype controls. ChIP-seq of histone modifications, generated in parallel, revealed genotype-specific colocalization of HTT with trimethylation of histone 3 lysine 27 (H3K27me3), a repressive chromatin mark. Near genes that are differentially regulated in HD, greater HTT occupancy in HttQ111/+ vs. wildtype mice predicted increased H3K27me3, reduced histone 3 lysine 4 (H3K4me3), a marker of poised and active promoters, and down-regulated gene expression. Altered huntingtin-chromatin interactions may therefore play a direct role in driving transcriptional dysregulation in HD.
2023-05-16 | GSE150748 | GEO
Project description:Mutation in the huntingtin (HTT) gene causes Huntington’s disease. Wild type Htt is essential for development as Htt knockout mice die at day E7.5. Increasing evidence suggests mutant Htt may alter neurogenesis and development of striatal neurons resulting in neuronal loss. Using mouse embryonic stem cells (mESCs), we examined the role of Htt in neural differentiation. We found Htt-null (HN) mESCs inefficient in generating neural stem cells. In contrast differentiation into progenitors of mesoderm and endoderm lineages was not affected. To investigate the basis for the lack of neural differentiation, we carried out gene expression profiling by RNA-seq to examine if genes involved in neural differentiation were dysregulated in HN mESCs.
2017-01-03 | GSE92905 | GEO
Project description:Single cell RNA-seq and bulk RNA-seq characterization of human induced pluripotent stem cell (hiPSCs) derived Huntington's disease organoids resembling the human striatum
2022-02-26 | GSE184255 | GEO
Project description:Huntington’s disease (HD) is a monogenetic neurodegenerative disorder caused by the expansion of a polyglutamine (polyQ) stretch in huntingtin (htt). Here we show that mutant htt reduces the transcription of insulin-like growth factor 1 (IGF-1) and leads to loss of IGF-1 in HD brains, HD mouse models and mutant htt-transgenic microglial cells. IGF-1 replacement therapy by transplantation of genetically engineered mouse neuronal precursor cells (mNPCs) in a mouse model of HD reverted the motor phenotype and countered striatal neuronal loss.
2018-10-01 | GSE19291 | GEO
Project description:Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder caused by a trinucleotide expansion in exon 1 of the huntingtin (Htt) gene. Cell death in HD occurs primarily in striatal medium spiny neurons (MSNs), but the involvement of specific MSN subtypes and of other striatal cell types remains poorly understood. To gain insight into cell type-specific disease processes, we studied the nuclear transcriptomes of 4,524 cells from the striatum of a genetically precise knock-in mouse model of the HD mutation, HttQ175/+, and from wildtype controls. We used 14-15-month-old mice, a time point roughly equivalent to an early stage of symptomatic human disease. Cell count distributions indicated selective loss of D2 MSNs and increased microglia in aged HttQ175/+ mice. Thousands of differentially expressed genes were distributed across most striatal cell types, including transcriptional changes in glial populations that are not apparent from RNA-seq of bulk tissue. Reconstruction of cell type-specific transcriptional networks revealed a striking pattern of bidirectional dysregulation for many cell type-specific genes. Typically, these genes were repressed in their primary cell type, yet de-repressed in other striatal cell types. Integration with existing epigenomic and transcriptomic data suggest that partial loss-of-function of the Polycomb Repressive Complex 2 (PRC2) may underlie many of these transcriptional changes, leading to deficits in the maintenance of cell identity across virtually all cell types in the adult striatum.
2020-07-11 | GSE154181 | GEO
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
Project description:In Huntington’s Disease, cellular toxicity is particularly caused by toxic protein fragments generated from the mutant huntingtin (HTT) protein. By modifying the HTT protein, we aim to reduce proteolytic cleavage and ameliorate the consequences of mutant HTT without lowering total HTT levels. To that end, we use an antisense oligonucleotide (AON) that targets HTT pre-mRNA and induces partial skipping of exon 12, which contains the critical caspase-6 cleavage site. Here, we show that AON-treatment can partially restore the phenotype of YAC128 mice, a mouse model expressing the full-length human HTT gene including 128 CAG-repeats. Wild-type and YAC128 mice were treated intracerebroventricularly with AON12.1, scrambled AON or vehicle starting at 6 months of age and followed up to 12 months of age, when MRI was performed and mice were sacrificed. AON12.1 treatment induced around 40% exon skip and protein modification. The phenotype on body weight and activity, but not rotarod, was restored by AON treatment. Genes differentially expressed in YAC128 striatum changed towards wild-type levels and striatal volume was preserved upon AON12.1 treatment. However, scrambled AON also showed a restorative effect on gene expression and appeared to generally increase brain volume.
2023-12-01 | GSE239312 | GEO
Project description:Dysregulation of the striatum is linked to multiple diseases including Huntington’s (HD), Parkinson’s, X-linked dystonia-parkinsonism (XDP), addiction, autism, and schizophrenia. Striatal medium spiny neurons (MSNs) make up 90% of the neuronal cell type in the striatum and are critical to motor control. The transcription factor Bcl11b (also known as CTIP2) is known to regulate of MSN differentiation, striatal striosome (patch) development and the architecture of the striatum during development. However, the function of Bcl11b adult striatal neurons in vivo has not been investigated. Therefore, we conditionally knocked out Bcl11b specifically in MSNs using D9-cre under the control of a regulatory elements of the mouse Ppp1r1b gene encoding DARPP-32 resulting in knockout around 5-6 weeks of age. Transcriptomic and behavioral analysis were performed on these mice.
2022-11-02 | GSE185476 | GEO
Project description:Despite 20 years since its discovery, the gene responsible for Huntington’s Disease, HTT, has still not had its function or transcriptional profile completely characterized. In response to a recent report by Ruzo et al. of several novel splice forms of HTT in human embryonic stem cell lines, we have analyzed a set of mRNA sequencing datasets from post mortem human brain from Huntington’s disease, Parkinson’s disease, and neurologically normal control subjects to evaluate support for previously observed and to identify novel splice patterns. A custom analysis pipeline produced supporting evidence for some of the results reported by two previous studies of alternative isoforms as well as identifying previously unreported splice patterns. All of the alternative splice patterns were of relatively low abundance compared to the canonical splice form.
2015-10-10 | GSE71191 | GEO