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Gene expression data from HD mutant and wild type ST14A cells, differentiated for 24 hours and treated with vehicle (DMSO) or with 5µM MIND4

ABSTRACT: Activation of cellular responses through the NRF2/KEAP1/ARE pathway is a promising therapeutic strategy to counter neurodegeneration. The present study identified a novel lead compound, MIND4, which induces canonical NRF2-dependent responses and is protective in primary neurons, neuronal slice cultures and a Drosophila model of Huntington’s disease (HD). In accord with the known anti-inflammatory effects of NRF2 activation, MIND4 and its structural analog, potently repressed an expression of inflammatory markers in activated microglial cells. MIND4 treatment significantly reduced levels of TNF-alpha in the cortex of symptomatic HD mice, demonstrating the neuroprotective anti-inflammatory potential of NRF2 activator in the CNS. A high affinity reversible binding of MIND4 ligands to the NRF2 inhibitor, KEAP1, was identified by a docking model and confirmed by mechanistic studies, suggesting a novel approach to activating the NRF2 pathway. The results offer a new therapeutic path for HD and other human diseases.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE49392 | GEO | 2013/08/01

SECONDARY ACCESSION(S): PRJNA213880

REPOSITORIES: GEO

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Gene expression data from HD mutant and wild type ST14A cells, differentiated for 24 hours and treated with vehicle (DMSO) or with 5M-BM-5M MIND4

Project description:Activation of cellular responses through the NRF2/KEAP1/ARE pathway is a promising therapeutic strategy to counter neurodegeneration. The present study identified a novel lead compound, MIND4, which induces canonical NRF2-dependent responses and is protective in primary neurons, neuronal slice cultures and a Drosophila model of HuntingtonM-bM-^@M-^Ys disease (HD). In accord with the known anti-inflammatory effects of NRF2 activation, MIND4 and its structural analog, potently repressed an expression of inflammatory markers in activated microglial cells. MIND4 treatment significantly reduced levels of TNF-alpha in the cortex of symptomatic HD mice, demonstrating the neuroprotective anti-inflammatory potential of NRF2 activator in the CNS. A high affinity reversible binding of MIND4 ligands to the NRF2 inhibitor, KEAP1, was identified by a docking model and confirmed by mechanistic studies, suggesting a novel approach to activating the NRF2 pathway. The results offer a new therapeutic path for HD and other human diseases. A total of 8 samples, HD mutant and wild type ST14A cells, stably expressing either a mutant expanded repeat (128Q) or wild type (26Q) 546 amino acid huntingtin fragment (a generous gift of E. Cattaneo) (Ehrlich et al., 2001)), 4 HD & 4 control, were used for drug treatment and array-based gene expression analysis. 4 samples, 2 HD and 2 Contol, were treated with 5M-BM-5M MIND4 with each pair ran as replicates. The other 4 samples, 2 HD and 2 Contol, were treated with DMSO with each pair ran as replicates.

2013-08-01 | E-GEOD-49392 | biostudies-arrayexpress

Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription

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Chronic activation of hepatic Nrf2 has no major effect on fatty acid and glucose metabolism in adult mice

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2016-09-01 | E-GEOD-80956 | biostudies-arrayexpress

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Project description:Temporal dynamics and mechanisms underlying epigenetic changes in Huntington’s disease (HD),a neurodegenerative disease primarily affecting the striatum, remain unclear. Using slow progressing HDknockinmice,we have generated chromatin immunoprecipitation coupled with sequencing data for RNA polymerase II and histone modifications associated with active enhancers (H3K27ac) and repressive chromatin (H3K27me3), from neuronal, non-neuronal and bulk striatal tissue at two early disease stages. Data integration with cell type-specific transcriptomic databases shows that the HD mutation early accelerates age-related reprogramming of neuronal and glial cell identities at both epigenetic and transcriptional levels. Circular chromosome conformation capture followed by sequencing data using HD mouse striatum showed alterations both at neuronal super-enhancer and CAG expanded disease loci. Using these data to model higher-order chromatin architecture indicated that HD CAG expansion mutation impairs chromatin insulation and gene regulation. Thus, both age-dependent and disease locus-specific mechanisms contribute to early remodelling of chromatin structure in HD striatum.

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