E-GEOD-55187
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: PRJNA238831
PROVIDER: E-GEOD-55187 | ExpressionAtlas | 2015-08-04
REPOSITORIES: ExpressionAtlas
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Project description:Partial phenotypic rescue of the Sesb1 mitochondrial ANT1 disease model in Drosophila
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Project description:The Personalized Discovery Process is the only program offering patients treatment recommendations based on an empirically constructed Drosophila "fly" model of their disease. Special committee selects one of the one of the few 2-3 FDA approved drug combinations or single agents that improved survival in the fly cancer model.
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Project description:The epitranscriptome plays a key regulatory role in cellular processes in health and disease, including ribosome biogenesis. Here, analysis of the human mitochondrial transcriptome shows that 2’-O-methylation is limited to residues of the mitoribosomal large subunit (mtLSU) 16S mt-rRNA, modified by MRM1, MRM2, and MRM3. Ablation of MRM2 leads to a severe impairment of the oxidative phosphorylation system, caused by defective mitochondrial translation and accumulation of mtLSU assembly intermediates. Structures of these particles (2.58Å) present disordered RNA domains, partial occupancy of bL36m and bound MALSU1:L0R8F8:mtACP anti-association module. Additionally, we present five mtLSU assembly states with different intersubunit interface configurations. Complementation studies demonstrate that the methyltransferase activity of MRM2 is dispensable for mitoribosome biogenesis. The Drosophila melanogaster orthologue, DmMRM2, is an essential gene, with its knock-down leading to developmental arrest. This work identifies a key late-stage quality control step during mtLSU assembly, ultimately contributing to the maintenance of mitochondrial homeostasis.
2021-12-19 | GSE179085 | 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-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.
2010-04-08 | E-GEOD-21237 | biostudies-arrayexpress
Project description:Cross-platform expression microarray performance in a mouse model of mitochondrial disease therapy
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Project description:MandibuloAcral Dysplasia associated to MTX2 gene (MADaM) is a recently described progeroid syndrome (accelerated aging disease) whose clinical manifestations include skin abnormalities, growth retardation, and cardiovascular diseases. We previously proposed that mtx-2-deficient C. elegans could be used as a model for MADaM and to support this, we present here our comprehensive phenotypic characterization of these worms using atomic force microscopy (AFM), transcriptomic, and oxygen consumption rate analyses. AFM analysis showed that young mtx-2-less worms had a significantly rougher, less elastic cuticle which becomes significantly rougher and less elastic as they age, and abnormal mitochondrial morphology. mtx-2 C. elegans displayed delayed development, decreased pharyngeal pumping, significantly reduced mitochondrial respiratory capacities, and transcriptomics analysis identified perturbations in the aging, TOR, and WNT-signaling pathways. The phenotypic characteristics of mtx-2 worms shown here are analogous to many of the human clinical presentations of MADaM and we believe this validates their use as a model which will allow us to uncover the molecular details of the disease and develop new therapeutics and treatments.
2024-09-13 | GSE276882 | GEO