Transcriptomics data of blood and brain from the YAC128 Huntington's disease mouse model [blood]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE169405 | GEO | 2021/12/21
REPOSITORIES: GEO
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Project description:Therapeutic development for Huntington's disease (HD) would benefit from a method to monitor disease progression and treatment efficacy, ideally using blood biomarkers. Previously, HD-specific signatures were identified in human blood which adequately represented signatures in human brain, showing biomarker potential. Since drug candidates are normally first screened in rodent models, we aimed to identify HD-signatures in blood and brain of YAC128 HD mice and validate these with our previously identified human signatures. In both brain and blood, we identified HD-associated modules using Weighted Gene Co-expression Network Analysis (WGCNA) representing various biological processes previously associated with HD. Disease-related processes in blood and brain showed substantial overlap, including processes related to protein modification, cell cycle, RNA splicing, nuclear transport and vesicle-mediated transport. Moreover, the disease-associated processes shared between mouse blood and brain were highly comparable to those previously identified in human blood and brain. In addition to shared pathology, we identified HD-associated blood modules showing blood-specific pathology.
2021-12-21 | GSE170997 | GEO
Project description:Huntington disease (HD) is an incurable neurodegenerative disease that is characterized by neuronal loss and astrogliosis. One hallmark of HD is the selective neuronal vulnerability of striatal medium spiny neurons and to date, the underlying mechanisms of this selective vulnerability have not been fully defined. Here, we employed a multi-omic approach including single nucleus RNAseq (snRNAseq), bulk RNAseq, lipidomics, CAG repeat length measurements, and multiplexed immunofluorescence on post-mortem brain tissue from multiple brain regions of HD and control donors. We defined a signature of genes that is driven by CAG repeat length and found it enriched in astrocytic and microglial genes. Moreover, weighted gene correlation network analysis showed loss of connectivity of astrocytic and microglial modules in HD and identified modules that correlated with CAG-repeat length which further implicated inflammatory pathways and metabolism. We performed lipidomic analysis of HD and control brains and identified several lipid species that correlate with HD grade, including ceramides and very long chain fatty acids. Integration of lipidomics and bulk transcriptomics identified a consensus gene signature that correlates with HD grade and HD lipidomic abnormalities and implicated the unfolded protein response pathway. Because astrocytes are critical for brain lipid metabolism and play important roles in regulating inflammation, we analyzed our snRNAseq dataset with an emphasis on astrocyte pathology. We found two main astrocyte types that spanned multiple brain regions; these types correspond to protoplasmic astrocytes, and fibrous-like, CD44-positive astrocytes. HD pathology was differentially associated with these cell types in a region-specific manner. One protoplasmic astrocyte cluster showed high expression of metallothionein genes, the depletion of which positively correlated with the depletion of vulnerable medium spiny neuronal clusters in the caudate nucleus. We confirmed that metallothioneins were increased in cingulate HD astrocytes but were unchanged or even decreased in caudate astrocytes. We combined existing genome-wide association studies (GWAS) with a GWA study conducted on HD patients from the original Venezuelan cohort and identified a single-nucleotide polymorphism in the metallothionein gene locus associated with delayed age of onset. Functional studies found that metallothionein overexpressing astrocytes are better able to buffer glutamate and were neuroprotective of induced pluripotent stem cells-derived HD MSNs as well as against rotenone-induced neuronal death in vitro. Finally, we found that metallothionein- overexpressing astrocytes increased the phagocytic activity of microglia in vitro and increased the expression of genes involved in fatty acid binding. Together, we identified an astrocytic phenotype that is regionally-enriched in less vulnerable brain regions that can be leveraged to protect neurons in HD.
2024-06-13 | GSE242197 | GEO
Project description:Huntington disease (HD) is an incurable neurodegenerative disease that is characterized by neuronal loss and astrogliosis. One hallmark of HD is the selective neuronal vulnerability of striatal medium spiny neurons and to date, the underlying mechanisms of this selective vulnerability have not been fully defined. Here, we employed a multi-omic approach including single nucleus RNAseq (snRNAseq), bulk RNAseq, lipidomics, CAG repeat length measurements, and multiplexed immunofluorescence on post-mortem brain tissue from multiple brain regions of HD and control donors. We defined a signature of genes that is driven by CAG repeat length and found it enriched in astrocytic and microglial genes. Moreover, weighted gene correlation network analysis showed loss of connectivity of astrocytic and microglial modules in HD and identified modules that correlated with CAG-repeat length which further implicated inflammatory pathways and metabolism. We performed lipidomic analysis of HD and control brains and identified several lipid species that correlate with HD grade, including ceramides and very long chain fatty acids. Integration of lipidomics and bulk transcriptomics identified a consensus gene signature that correlates with HD grade and HD lipidomic abnormalities and implicated the unfolded protein response pathway. Because astrocytes are critical for brain lipid metabolism and play important roles in regulating inflammation, we analyzed our snRNAseq dataset with an emphasis on astrocyte pathology. We found two main astrocyte types that spanned multiple brain regions; these types correspond to protoplasmic astrocytes, and fibrous-like, CD44-positive astrocytes. HD pathology was differentially associated with these cell types in a region-specific manner. One protoplasmic astrocyte cluster showed high expression of metallothionein genes, the depletion of which positively correlated with the depletion of vulnerable medium spiny neuronal clusters in the caudate nucleus. We confirmed that metallothioneins were increased in cingulate HD astrocytes but were unchanged or even decreased in caudate astrocytes. We combined existing genome-wide association studies (GWAS) with a GWA study conducted on HD patients from the original Venezuelan cohort and identified a single-nucleotide polymorphism in the metallothionein gene locus associated with delayed age of onset. Functional studies found that metallothionein overexpressing astrocytes are better able to buffer glutamate and were neuroprotective of induced pluripotent stem cells-derived HD MSNs as well as against rotenone-induced neuronal death in vitro. Finally, we found that metallothionein- overexpressing astrocytes increased the phagocytic activity of microglia in vitro and increased the expression of genes involved in fatty acid binding. Together, we identified an astrocytic phenotype that is regionally-enriched in less vulnerable brain regions that can be leveraged to protect neurons in HD.
2024-06-13 | GSE242195 | GEO
Project description:To gain insight into how mutant Huntingtin (mHTT) CAG repeat length may modify Huntington’s disease (HD) pathogenesis, we profiled mRNA in over 600 brain and peripheral tissue samples from HD knock-in mice with increasing CAG repeat length. We find repeat length dependent transcriptional signatures are prominent in the striatum, less so in cortex, and minimal in the liver. Co-expression network analyses reveal 13 striatal and 5 cortical modules that are highly correlated with CAG length and age, and that are preserved in HD models and some in the patients. Top striatal modules implicate mHTT CAG length and age in graded impairment of striatal medium spiny neuron identity gene expression and in dysregulation of cAMP signaling, cell death, and protocadherin genes. Importantly, we used proteomics to confirm 790 genes and 5 striatal modules with CAG length-dependent dysregulation at both RNA and protein levels and validated 21 striatal module genes as modifiers of mHtt toxicities in vivo.
2016-02-16 | PXD003442 | Pride
Project description:Transcriptional dysregulation is well documented in Huntington’s disease (HD) post-mortem brain. We previously identified gene expression profiles from both symptomatic and asymptomatic HD prefrontal cortex which characterize the effects of degeneration in disease versus normal brains. Transcriptional dysregulation in HD brain is well documented by these studies and others, but the extent and causes of this dysregulation remain unknown. Here, we present a large ribo-depleted RNA sequencing (rdRNA-Seq) dataset and novel bioinformatic methodology to further characterize transcriptional dysregulation in HD brain as it relates to disease variables, including CAG repeat size, age of symptom onset, and rate of neurodegeneration.
2020-10-28 | GSE159940 | GEO
Project description:Direct neuronal conversion of fibroblasts from Huntington’s disease (HD) patients to striatal medium spiny neurons (MSNs) has been shown to recapitulate neurodegenerative pathology of HD. Here, we carried out comparative analyses between reprogrammed MSNs from patients at different disease stages to investigate age-associated molecular processes driving neurodegeneration. We found that neuronal death was manifested in reprogrammed MSNs from symptomatic HD patients (HD-MSNs) compared to MSNs derived from younger, pre-symptomatic patients (pre-HD-MSNs) and healthy controls. Dissecting the differential cellular state between HD-MSNs and pre-HD-MSNs by transcriptome and chromatin accessibility analyses identified miR-29b-3p, whose age-associated upregulation impairs autophagic function via human-specific targeting of STAT3. Reducing miR-29b-3p or treating with G2-115, a glibenclamide analog, increased the resilience of HD-MSNs against neurodegeneration by promoting autophagy, demonstrating that the autophagic decline during aging in HD underlies MSN degeneration and pointing to potential approaches for enhancing autophagy and resilience of MSNs against degeneration in HD.
2022-09-15 | GSE194242 | GEO
Project description:Direct neuronal conversion of fibroblasts from Huntington’s disease (HD) patients to striatal medium spiny neurons (MSNs) has been shown to recapitulate neurodegenerative pathology of HD. Here, we carried out comparative analyses between reprogrammed MSNs from patients at different disease stages to investigate age-associated molecular processes driving neurodegeneration. We found that neuronal death was manifested in reprogrammed MSNs from symptomatic HD patients (HD-MSNs) compared to MSNs derived from younger, pre-symptomatic patients (pre-HD-MSNs) and healthy controls. Dissecting the differential cellular state between HD-MSNs and pre-HD-MSNs by transcriptome and chromatin accessibility analyses identified miR-29b-3p, whose age-associated upregulation impairs autophagic function via human-specific targeting of STAT3. Reducing miR-29b-3p or treating with G2-115, a glibenclamide analog, increased the resilience of HD-MSNs against neurodegeneration by promoting autophagy, demonstrating that the autophagic decline during aging in HD underlies MSN degeneration and pointing to potential approaches for enhancing autophagy and resilience of MSNs against degeneration in HD.
2022-09-15 | GSE194241 | GEO
Project description:Huntington’s Disease is a neurodegenerative disorder caused by a CAG expansion in exon1 of the huntingtin (Htt) gene. The resulting polyglutamine expansion in the ubiquitously expressed mutant Htt (mHtt) protein leads to selective neurodegeneration. In this study we set out to identify interacting proteins of full length wild-type and mHtt protein in the mice cortex brain region in order to get a better understanding of the processes involved in HD pathology.
2021-06-21 | PXD024254 | Pride
Project description:Blood is a very accessible tissue and as such constitutes a useful source of clinical markers. While it is obvious that metabolic disorders leave a clear mark in blood, it is not so clear whether this is the case for neurodegenerative diseases of the brain. Markers for neurodegenerative diseases are potentially useful to advance our understanding of the mechanisms involved in these diseases but are nearly impossible to obtain from living patients. To find whether altered gene expression could be found in blood of patients with a neurodegenerative disease, we collected blood samples from patients of Huntington’s disease (HD) and analysed their differences versus controls in terms of gene expression by RNA-seq analysis. We observed significant differential expression of a set of genes, with genes upregulated in patients enriched in immune response related functions and inflammatory response. We conclude that it is possible to detect changes in the expression of RNAs in blood from patients of HD and that this reflects the inflammatory pathology associated to the disease.
2017-09-15 | GSE61405 | GEO
Project description:Alcohol consumption is known to lead to gene expression changes in the brain. After performing gene co-expression network analysis (WGCNA) of genome-wide mRNA and microRNA expressions in the Nucleus Accumbens (NAc) from subjects with alcohol dependence (AD) and matched controls six mRNA and three miRNA modules significantly correlated with AD after Bonferroni correction (adj. p? 0.05) were identified. Cell-type-specific transcriptome analysis revealed two of the mRNA modules to be enriched for neuronal specific marker genes and downregulated in AD, whereas the remaining four were enriched for astrocyte and microglial specific marker genes and were upregulated in AD. Using gene set enrichment analysis, the neuronal specific modules were enriched for genes involved in oxidative phosphorylation, mitochondrial dysfunction and MAPK signaling, while the glial-specific modules were enriched mostly for genes involved in processes related to immune functions, i.e. reactome cytokine signaling in immune system (all adj. p? 0.05). In the mRNA and miRNA modules, 461 and 25 candidate hub genes were identified, respectively. In contrast to the expected miRNAs’ biological functions, the correlation analyses between mRNA and miRNA hub genes revealed a significantly higher number of positive than negative correlations (chi-square p? 0.0001). At FDR? 0.1, integration of the mRNA and miRNA hubs genes expression with genome-wide genotypic data identified 591 cis-eQTLs and 62 cis-eQTLs for the mRNA and miRNA hubs, respectively. Adjusting for the number of tests, the mRNA cis-eQTLs were significantly enriched for AD GWAS signals in the Collaborative Study on Genetics of Alcohol (COGA) sample (adj. p=0.024), providing a novel biological role for these association signals. In conclusion, our study identified coordinated mRNA and miRNA co-expression changes in the NAc of AD subjects, and our genetic (cis-eQTL) analysis provides novel insights into the etiological mechanisms of AD. Tissue samples were received from the Australian Brain Donor Programs New South Wales Tissue Resource Centre, which is supported by The University of Sydney, National Health and Medical Research Council of Australia, Schizophrenia Research Institute, National Institute of Alcohol Abuse and Alcoholism, and the New South Wales Department of Health. Cases were excluded if they had an infectious disease (i.e. HIV/AIDS, hepatitis B or C, or Creutzfeldt-Jakob disease), an unsatisfactory agonal status determined from the circumstances surrounding the death, post-mortem delays >48 hours, or significant head injury. In addition to case status, age, sex, ethnicity, brain weight, brain pH, post-mortem interval (PMI), tissue hemisphere, clinical cause of death, blood toxicology at time of death, smoking status, neuropathology and liver pathology were also provided for each subject. MiRNA and mRNA expression in 18 matched case-control pairs (N=36) with sample RINs ?6 were assessed on the Affymetrix GeneChip® Human Genome U133A 2.0 (HG-U133A 2.0) and Affymetrix GeneChip miRNA 3.0 microarray.
2015-05-22 | E-GEOD-62699 | biostudies-arrayexpress