Cell-intrinsic glial pathology is conserved across human and murine models of Huntington Disease
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PROVIDER: PRJNA645187 | ENA |
REPOSITORIES: ENA
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Project description:hESC-based human glial chimeric mice reveal glial differentiation defects in Huntington disease
| PRJNA414457 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-04-07 | GSE154141 | GEO
Project description:Gene expression profile comparison from fibroblasts of Huntington individuals and normal ones We used microarrays to detail the global gene expression of fibroblasts from Huntington patients Comparison between six Huntington human fibroblasts and three normal controls. All individuals were aged and sex matched. In fact they are all males with the subsequent ages: 28, 48, 57 for the controls and 38, 63, 57, 47, 38, 37 for the HD patients. The average age is comparable.
2013-03-28 | E-GEOD-45516 | biostudies-arrayexpress
Project description:Gene expression profile comparison from fibroblasts of Huntington individuals and normal ones We used microarrays to detail the global gene expression of fibroblasts from Huntington patients
2013-03-28 | GSE45516 | GEO
Project description:Huntington’s disease (HD) is characterized by hypomyelination as well as by neuronal loss. To assess the basis for white matter involution in HD, we generated bipotential glial progenitor cells (GPCs) from human embryonic stem cells (hESCs), derived from either huntingtin (mHTT)-mutant embryos or normal controls, and performed RNA sequence analysis to assess mHTT-dependent changes in gene expression. In hGPCs derived from 3 distinct mHTT-expressing hESC lines, a set of transcription factors associated with glial differentiation and myelin synthesis was sharply down-regulated, relative to normal hESC GPCs. In particular, NKX2.2, OLIG2, SOX10 and MYRF were all suppressed, with the consequent diminution of myelinogenesis-associated transcription. Accordingly, when mHTT-expressing hGPCs were transplanted into hypomyelinated shiverer mice, the resultant mHTT glial chimeras were hypomyelinated. The mHTT hGPCs also manifested impaired astrocytic differentiation, and developed abnormal fiber domain architecture. These data suggest that white matter involution in HD is a product of a cell-autonomous mHTT-dependent suppression of both astrocytic and oligodendrocytic differentiation by affected GPCs.
2018-11-10 | GSE105041 | GEO
Project description:Human glial progenitor cells (hGPCs) are highly migratory, and glial replacement has the potential to treat those neurological disorders in which astrocytic and oligodendrocytic pathology are contributory. Yet it remains unknown whether allografted human glia can out compete diseased cells to achieve therapeutic replacement in the adult human brain.To that end, we engrafted healthy wild-type (WT) hGPCs into the striata of adult mice that had been earlier chimerized neonatally with mutant HTT-expressing hGPCs generated from Huntington disease (HD)-derived human embryonic stemcells. The WT hGPCs effectively out competed and ultimately eliminated their HD counterparts, repopulating the host striata with healthy humanglia. Single-cell transcriptomics revealed that WT hGPCs actively assumed a dominant competitor phenotype upon interaction with their resident HD counter parts.The outcomes of clonal competition depended primarily upon the age difference between competing clones, in that adult-transplanted WT GPCs effectively out competed their isogenic WT counter parts that had been transplanted neonatally, and which were thus necessarily older.These data suggest that both aged and diseased human glia may be broadly replaced in the adult brain by younger and healthier human glial progenitor cells.
2023-04-04 | GSE206322 | GEO
Project description:Accumulation of cytoplasmic inclusions of TAR-DNA binding protein 43 (TDP-43) is seen in both neurons and glia in a range of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer’s disease (AD). Disease progression involves non-cell autonomous interactions among multiple cell types, including neurons, microglia and astrocytes. We investigated the effects in Drosophila of inducible, glial cell type-specific TDP-43 overexpression, a model that causes TDP-43 protein pathology including loss of nuclear TDP-43 and accumulation of cytoplasmic inclusions. We report that TDP-43 pathology in Drosophila is sufficient to cause progressive loss of each of the 5 glial sub-types. But the effects on organismal survival were most pronounced when TDP-43 pathology was induced in the perineural glia (PNG) or astrocytes. In the case of PNG, this effect is not attributable to loss of the glial population, because ablation of these glia by expression of pro-apoptotic reaper expression has relatively little impact on survival. To uncover underlying mechanisms, we used cell-type-specific nuclear RNA sequencing to characterize the transcriptional changes induced by pathological TDP-43 expression. We identified numerous glial cell-type specific transcriptional changes. Notably, SF2/SRSF1 levels were found to be decreased in both PNG and in astrocytes. We found that further knockdown of SF2/SRSF1 in either PNG or astrocytes lessens the detrimental effects of TDP-43 pathology on lifespan, but extends survival of the glial cells. Thus TDP-43 pathology in astrocytes or PNG causes systemic effects that shorten lifespan and SF2/SRSF1 knockdown rescues the loss of these glia, and also reduces their systemic toxicity to the organism.
2023-09-08 | GSE242209 | GEO
Project description:Genetic studies have suggested a role for glial pathology in the genesis of schizophrenia (SCZ). To assess the nature of SCZ-associated human glial dysfunction in vivo, we established human glial chimeric mice using glial progenitor cells (GPCs) produced from induced pluripotential cells (hiPSCs), derived from patients with juvenile-onset schizophrenia or healthy controls. To this end, hiPSC GPCs were implanted neonatally into either immunodeficient myelin wild-type mice, in which donor GPCs remained as progenitors or became astrocytes, or into myelin-deficient shiverer mice, in which the GPCs also gave rise to oligodendrocytes. When implanted into shiverers, the SCZ-derived GPCs exhibited less expansion in the white matter than did control GPCs, instead migrating prematurely into the cortex. The SCZ GPC-transplanted shiverers were consequently hypomyelinated relative to control GPC-engrafted mice. When established instead in myelin wild-type hosts, the SCZ hiPSC glial chimeras manifested markedly delayed and diminished astrocytic differentiation, which was associated with diminished prepulse inhibition and an aberrant behavioral phenotype across multiple modalities. Accordingly, RNA-seq revealed significant differences in both glial differentiation-associated and synaptic gene expression by SCZ GPCs. These data suggest a potent contribution of cell-autonomous glial dysfunction to the development of schizophrenia, and provide a model for the in vivo assessment of human glial pathology in this disorder.
2017-07-20 | GSE86906 | GEO
Project description:Huntington disease is a severe neurological disorder caused by an abnormal polyglutamine expansion in the N-terminal of the huntingtin protein. Here we show that breast tumours appear earlier when mutant huntingtin is expressed in an activated polyomavirus middle T antigen (PyVT) mouse breast cancer model as compared to the control mice expressing wild-type huntingtin. Tumours bearing mutant huntingtin have a modified gene expression pattern revealing increases in the IGF-1/Akt signalling, epithelial-mesenchymal transition and metastatic properties. Indeed, polyQ-huntingtin expressing tumours show hyper-activation of Akt pathway. Also, when mutant huntingtin is expressed, cancer cells in culture change morphology and the levels of cell adhesion and mesenchymal markers are affected in primary tumour or corresponding derived cells. As a consequence, PyVT induced lung metastasis is higher in Huntington disease mice than in the control mice. Finally, analysis of cases of Huntington disease patients developing breast cancer may suggest an increased aggressiveness of breast cancer when compared to the control population. 8 Total samples were analyzed: 4 x MMTV-PyVT/HdhQ7/Q7 breast tumours; 4 x MMTV-PyVT/HdhQ111/Q111 breast tumours;
2014-04-14 | E-GEOD-28685 | biostudies-arrayexpress
Project description:Huntington’s disease (HD) and juvenile-onset schizophrenia (SCZ) have long been regarded as distinct disorders. However, both manifest cell-intrinsic abnormalities in glial differentiation, with resultant astrocytic dysfunction and hypomyelination. To assess whether a common mechanism might underlie the similar glial pathology of these otherwise disparate conditions, we utilized comparative correlation network approaches to analyze RNA-seq data from human glial progenitor cells (hGPCs) produced from disease-derived pluripotent stem cells. We identified gene sets preserved between HD and SCZ hGPCs yet distinct from normal controls, that included 174 highly-connected genes in the shared disease-associated network, focused on genes involved in synaptic signaling. These synaptic genes were largely suppressed in both SCZ and HD hGPCs, and gene regulatory network analysis identified a core set of upstream regulators of this network, of which OLIG2 and TCF7L2 were prominent. Among their downstream targets, ADGRL3, a modulator of glutamatergic synapses, was notably suppressed in both SCZ and HD hGPCs. ChIP-seq confirmed that OLIG2 and TCF7L2 each bound to the regulatory region of ADGRL3, whose expression was then rescued by lentiviral overexpression of these transcription factors. These data suggest that the disease-associated suppression of OLIG2 and TCF7L2-dependent transcription of glutamate signaling regulators may impair glial receptivity to neuronal glutamate. The consequent loss of activity-dependent mobilization of hGPCs may yield deficient oligodendrocyte production, and hence the hypomyelination noted in these disorders, as well as the disrupted astrocytic differentiation and attendant synaptic dysfunction associated with each. Together, these data highlight the importance of convergent glial molecular pathology in both the pathogenesis and phenotypic similarities of two otherwise unrelated disorders, HD and SCZ.
2024-05-08 | GSE188561 | GEO