Cell Type-Specific Transcriptomics Reveals that Mutant Huntingtin Leads to Mitochondrial RNA Release and Neuronal Innate Immune Activation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE152058 | GEO | 2020/07/17
REPOSITORIES: GEO
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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.
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Project description:Huntington Disease (HD) is a dominantly inherited, relentlessly progressive neurodegenerative disease. Caused by a polyglutamine expansion in the mutant huntingtin protein (mhtt), HD pathogenesis impairs function in the cerebral cortex and in medium spiny neurons of the striatum and involves transcriptional dysregulation of a number of genes. Of these genes, silencing of genes related to mitochondrial function is believed to explain metabolic dysfunction in rodent models of HD. Here we show that transglutaminase 2 (TG2), which is upregulated in HD, exacerbates transcriptional dysregulation by acting as a selective corepressor of nuclear genes. TG2 inhibition by RNA knockdown, genetic deletion, or administration of a novel irreversible, peptide-based TG2 inhibitor (ZDON) de-repressed two established regulators of mitochondrial function, PGC-1? and cytochrome c in a cell model of HD. TG2 must localize to non-coding or coding regions of these mitochondrial metabolic genes to silence their transcription. As expected, TG2 inhibition reversed the increased susceptibility of HD mouse cells and human HD myoblasts to the mitochondrial toxin, 3-nitroproprionic acid (3-NP); however, protection mediated by TG2 inhibition was not associated with improved mitochondrial bioenergetics. Indeed, an unbiased array analysis indicated that TG2 inhibition leads to normalization of not only mitochondrial genes but of nearly 40% of genes that are dysregulated in HD mouse striatal neurons, including chaperone and histone genes. Indeed, TG2 interacts directly with Histone 3 in the nucleus. Moreover, TG2 inhibition significantly attenuated photoreceptor degeneration in a Drosophila model of HD and protected mouse HD striatal neurons (YAC128) from NMDA- induced toxicity. Altogether these findings demonstrate that TG2 mediates its deleterious effects in HD by contributing to broad transcriptional dysregulation of genes representing many cellular functions. These studies define a novel HDAC-independent epigenetic strategy for treating neurodegeneration. To evaluate the effect of TG2 inhibition (treatment with ZDON, Boc-DON, CystamineA, and Control) in striatal cell lines from a transgenic model of Huntington disease (Q111) vs. control (Q7). One sample (WT.boc.3, 4068264015_G) failed the QC test and was excluded from further analyses.
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Project description:Glial pathology has been implicated as a causal contributor to the dysfunction and death of striatal neurons that characterizes Huntington disease. In this study, we investigated mutant HTT (mHTT)-associated changes in gene expression by both mouse and human striatal astrocytes. Mouse striatal astrocytes were FACS-sorted from two distinct models, R6/2 and zQ175 mice, which respectively express exon1-only truncated or full-length HTT, while human astrocytes were generated from either hESCs expressing full-length mHTT, or fetal striatal glia transduced with exon1-only mHTT. Comparison of differential gene expression between each of these conditions and their normal HTT controls, and to one another, revealed astrocyte-specific alterations in both truncated and full-length mHTT models that were shared by both species, yet with differences that clearly distinguished glia derived from each model. Overlap of these data sets revealed that the patterns of mHTT-associated transcriptional dysregulation depended not only upon species, but also upon whether the astroglia expressed truncated or full-length mHTT. These data revealed a common set of conserved, mHTT-associated dysregulated pathways that may present targets for the rescue of glial pathology in HD, while revealing that the gene expression of glia expressing truncated mHTT may differ substantially from that of glia expressing full-length mHTT.
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Project description:Glial pathology has been implicated as a causal contributor to the dysfunction and death of striatal neurons that characterizes Huntington disease. In this study, we investigated mutant HTT (mHTT)-associated changes in gene expression by both mouse and human striatal astrocytes. Mouse striatal astrocytes were FACS-sorted from two distinct models, R6/2 and zQ175 mice, which respectively express exon1-only truncated or full-length HTT, while human astrocytes were generated from either hESCs expressing full-length mHTT, or fetal striatal glia transduced with exon1-only mHTT. Comparison of differential gene expression between each of these conditions and their normal HTT controls, and to one another, revealed astrocyte-specific alterations in both truncated and full-length mHTT models that were shared by both species, yet with differences that clearly distinguished glia derived from each model. Overlap of these data sets revealed that the patterns of mHTT-associated transcriptional dysregulation depended not only upon species, but also upon whether the astroglia expressed truncated or full-length mHTT. These data revealed a common set of conserved, mHTT-associated dysregulated pathways that may present targets for the rescue of glial pathology in HD, while revealing that the gene expression of glia expressing truncated mHTT may differ substantially from that of glia expressing full-length mHTT.
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Project description:Selective degeneration of striatal projection neurons is one of the main features of Huntington’s disease (HD). The differences between vulnerable and resilient striatal cell types and cell type-specific molecular events associated with HD progression have not been established. Here we employed fluorescence-activated nuclear sorting (FANS) and deep molecular profiling to gain insight into the properties of different cell types of the human striatum in HD and control donors.
2023-12-04 | GSE227729 | GEO
Project description:Huntington Disease (HD) is a dominantly inherited, relentlessly progressive neurodegenerative disease. Caused by a polyglutamine expansion in the mutant huntingtin protein (mhtt), HD pathogenesis impairs function in the cerebral cortex and in medium spiny neurons of the striatum and involves transcriptional dysregulation of a number of genes. Of these genes, silencing of genes related to mitochondrial function is believed to explain metabolic dysfunction in rodent models of HD. Here we show that transglutaminase 2 (TG2), which is upregulated in HD, exacerbates transcriptional dysregulation by acting as a selective corepressor of nuclear genes. TG2 inhibition by RNA knockdown, genetic deletion, or administration of a novel irreversible, peptide-based TG2 inhibitor (ZDON) de-repressed two established regulators of mitochondrial function, PGC-1α and cytochrome c in a cell model of HD. TG2 must localize to non-coding or coding regions of these mitochondrial metabolic genes to silence their transcription. As expected, TG2 inhibition reversed the increased susceptibility of HD mouse cells and human HD myoblasts to the mitochondrial toxin, 3-nitroproprionic acid (3-NP); however, protection mediated by TG2 inhibition was not associated with improved mitochondrial bioenergetics. Indeed, an unbiased array analysis indicated that TG2 inhibition leads to normalization of not only mitochondrial genes but of nearly 40% of genes that are dysregulated in HD mouse striatal neurons, including chaperone and histone genes. Indeed, TG2 interacts directly with Histone 3 in the nucleus. Moreover, TG2 inhibition significantly attenuated photoreceptor degeneration in a Drosophila model of HD and protected mouse HD striatal neurons (YAC128) from NMDA- induced toxicity. Altogether these findings demonstrate that TG2 mediates its deleterious effects in HD by contributing to broad transcriptional dysregulation of genes representing many cellular functions. These studies define a novel HDAC-independent epigenetic strategy for treating neurodegeneration.
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