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RNA-sequencing of brain microvascular endothelial cell dysfunction in an isogenic juvenile iPSC model of Huntington’s disease

ABSTRACT: Huntington's disease (HD) is associated with dysfunction of the blood-brain barrier, including brain microvasscular endothelial cells (BMECs). We report changes in gene expression of induced pluripotent stem cells (iPSCs) and iPSC-derived brain microvascular endothelial cell-like cells (iBMECs) derived from an isogenic pair of iPSCs with either 180 (HD-corrected) or 18 (HD180) CAG repeats in the HTT gene.

ORGANISM(S): Homo sapiens

PROVIDER: GSE194416 | GEO | 2022/02/01

REPOSITORIES: GEO

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Human Huntington’s Disease iPSC-derived cortical neurons display altered transcriptomics, morphology and electrophysiological maturation

Project description:Huntington's disease (HD) is a neurodegenerative disease caused by an expanded CAG repeat in the Huntingtin (HTT) gene. Induced pluripotent stem cell (iPSC) models of HD provide an opportunity to study the mechanisms underlying disease pathology in patient tissues relevant to disease. Murine studies have demonstrated that HTT is intricately involved in corticogenesis, and mutant (mt) HTT cannot compensate for the loss of non-CAG-expanded HTT. However, the critical effect of mtHTT in human corticogenesis has not yet been specifically explored and due to inherent differences in cortical development and timing between humans and mice. We therefore differentiated HD and non-diseased iPSCs into functional cortical neurons. While HD patient iPSCs can be successfully differentiated towards a cortical fate in culture, the resulting neurons display transcriptomic, morphological and functional phenotypes indicative of altered neurodevelopment. This is the first demonstration of altered corticogenesis from HD human patient cells, further supporting the potential neurodevelopmental aspect of HD.

2018-09-29 | GSE109534 | GEO

The ubiquitin ligase UBR5 suppresses proteostasis collapse in immortal pluripotent stem cells and Huntington’s disease models

Project description:Pluripotent stem cells undergo unlimited self-renewal while maintaining their potential to differentiate into post-mitotic cells with an intact proteome, a capacity that demands a highly induced proteostasis network. As such, induced pluripotent stem cells (iPSCs) suppress the aggregation of polyQ-expanded huntingtin (HTT), the mutant protein underlying Huntington’s disease (HD). Here we show that proteasome activity determines HTT levels, preventing the accumulation of polyQ-expanded aggregates in iPSCs from HD patients (HD-iPSCs). iPSCs exhibit intrinsic high levels of UBR5, an E3 ubiquitin ligase that we find required for proteasomal degradation of both normal and mutant HTT. When UBR5 fails to monitor HTT proteostasis, the concomitant up-regulation of HTT expression particularly results in polyQ-expanded aggregation in HD-iPSCs. Moreover, UBR5 knockdown hastens protein aggregation and neurotoxicity in polyQ-expanded invertebrate models. Notably, ectopic expression of UBR5 is sufficient to induce polyubiquitination and degradation of mutant HTT, reducing polyQ-expanded aggregates in HD cell models. However, UBR5 is dispensable for the proteostasis of other aggregation-prone proteins linked with Machado-Joseph disease or amyotrophic lateral sclerosis in iPSCs. Besides its role in HTT regulation, we find that intrinsic high levels of UBR5 also determine the global proteostatic ability of iPSCs preventing aggresome formation, suggesting a role in the control of misfolded proteins ensued from normal metabolism. Thus, our findings indicate UBR5 as a central component of super-vigilant proteostasis of iPSCs with the potential to correct proteostatic deficiencies in HD.

2018-06-14 | PXD009803 | Pride

RNA sequencing of human iPSC-derived brain microvascular endothelial cells.

Project description:Induced pluripotent stem cells were differentiated to brain microvascular endothelial cells (BMECs) using previously published protocols with minor changes. RNA was collected from purified BMECs after barrier induction and submitted for sequencing.

2020-12-31 | E-MTAB-8802 | biostudies-arrayexpress

Alterations in the tyrosine and phenylalanine pathways revealed by biochemical profiling in cerebrospinal fluid of Huntington’s disease subjects

Project description:Huntington's disease (HD) is a severe neurological disease leading to psychiatric symptoms, motor impairment and cognitive decline. The disease is caused by a CAG expansion in the huntingtin (HTT) gene, but how this translates into the clinical phenotype of HD remains elusive. Using liquid chromatography mass spectrometry, we analyzed the metabolome of cerebrospinal fluid (CSF) from premanifest and manifest HD subjects as well as control subjects. Inter-group differences revealed that the tyrosine metabolism, including tyrosine, thyroxine, L-DOPA and dopamine, was significantly altered in manifest compared with premanifest HD. These metabolites demonstrated moderate to strong associations to measures of disease severity and symptoms. Thyroxine and dopamine also correlated with the five year risk of onset in premanifest HD subjects. The phenylalanine and the purine metabolisms were also significantly altered, but associated less to disease severity. Decreased levels of lumichrome were commonly found in mutated HTT carriers and the levels correlated with the five year risk of disease onset in premanifest carriers. These biochemical findings demonstrates that the CSF metabolome can be used to characterize molecular pathogenesis occurring in HD, which may be essential for future development of novel HD therapies.

2019-06-21 | MTBLS749 | MetaboLights

G3BP1-dependent suppression of polyglutamine aggregation in Huntington’s models and its failure upon stress granule formation

Project description:To define the interactome of huntingtin protein (HTT) in human neurons, we assessed interactors of HTT with coimmunoprecipitation experiments with huntingtin antibody or polyqlutamine antibody (it only recognizes mutant huntingtin protein with abnormal polyqlutamine expansion) in striatal neurons differentiated from control and patient-derived iPSC lines (HD-iPSCs). GFP antibody used as a negative control.

2022-12-02 | PXD037618 | Pride

RNA-Targeting CRISPR/Cas13d System Alleviates Disease-Related Phenotypes in Pre-clinical Models of Huntington’s Disease (Human).

Project description:Huntington's disease (HD) is a fatal, dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in exon 1 of the huntingtin (HTT) gene. Although the pathogenesis of HD remains complex, the CAG-expanded (CAGEX) HTT mRNA and protein ultimately causes disease through a toxic gain-of-function mechanism. As the reduction of pathogenic mutant HTT mRNA is beneficial as a treatment, we developed a mutant allele-sensitive CAGEX RNA-targeting CRISPR-Cas13d system (Cas13d/CAGEX) that eliminates toxic CAGEX RNA in HD patient-derived fibroblasts and iPSC-derived striatal neurons. We show that intrastriatal delivery of Cas13d/CAGEX via a single adeno-associated viral vector, serotype 9 (AAV9) mediates significant and selective reduction of mutant HTT mRNA and protein levels within the striatum of heterozygous zQ175 mice, an established mouse model of HD. Moreover, the reduction of mutant HTT mRNA renders a sustained partial reversal of HD phenotypes, including improved motor coordination, attenuated striatal atrophy, and reduction of mutant HTT protein aggregates. Importantly, phenotypic improvements were durable for at least 8 months without gross or behavioral adverse effects, and with minimal off-target interactions of Cas13d/CAGEX in the mouse transcriptome. Taken together, we demonstrate a proof-of-principle of an RNA-targeting CRISPR/Cas13d system as a therapeutic approach for HD, a strategy with broad implications for the treatment of other dominantly inherited neurodegenerative disorders.

2022-11-15 | GSE214108 | GEO

RNA-Targeting CRISPR/Cas13d System Alleviates Disease-Related Phenotypes in Pre-clinical Models of Huntington’s Disease (Mouse).

2022-11-15 | GSE214109 | GEO

RNA-seq expression data from Human iPSC-derived Brain Microvascular Endothelial-like Cells (iBMECs)

Project description:Comparison of Human iPSC-derived Brain Microvascular Endothelial-like Cells (iBMECs) grown in poly(dimethylsiloxane) tissue chips. Data contains RNA-seq profiles of iBMECs exposed to various levels of shear stress ranging from 0, 0.01, 0.5, and 2.4 dyn/cm2; as well as RNA-seq profiles of FACS sorted iBMECs cultured alone or with primary human astrocytes and pericytes or with iPSC-derived neural progenitor cells.

2019-06-05 | GSE129290 | GEO

RNA-sequencing of iPSC-derived blood-brain barrier cell types across microenvironments

Project description:The blood-brain barrier (BBB) is lined by brain microvascular endothelial cells (BMECs) which regulate transport into and out of the brain. We used human induced pluripotent stem cell (iPSC)-derived cell types to model BBB function within 2D and 3D in vitro models. We compare gene expression between different iPSC-derived cell types, and specifically profile the response of iPSC-derived BMEC-like cells (iBMECs) to differentiation media volume, microenvironmental cues, and cytokines.

2022-01-30 | GSE195519 | GEO

Spatiotemporal proteomic profiling of Huntington's disease mice reveals widespread loss of protein function

Project description:Huntington's disease (HD) is characterized by the aggregation of polyglutamine-expanded huntingtin (HTT), proceeding from soluble oligomers to end-stage inclusions. The molecular mechanisms of how protein aggregation leads to neuronal dysfunction are not well understood. We employed mass spectrometry-based quantitative proteomics to dissect spatiotemporal mechanisms of neurodegeneration using the R6/2 mouse model of HD. We show that extensive remodeling of the soluble brain proteome correlates with changes in insoluble aggregate formation during disease progression. In-depth characterization of HTT inclusion bodies uncovered an unprecedented complexity of several hundred proteins. Sequestration to inclusions was dependent on protein expression levels and the presence of aggregation-prone amino acid sequence features, such as low-complexity regions or coiled-coil domains. Overexpression of several sequestered proteins ameliorated HTT toxicity and modified the aggregation behavior in an in vitro model of HD. Our study provides a comprehensive and spatiotemporally-resolved proteome resource of HD progression, indicating that widespread loss of protein function contributes to aggregate-mediated toxicity.

2017-11-24 | PXD004973 | Pride

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