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Selected Spt5-Pol II inhibitors effectively relieve Huntington’s disease neuropathology and slow down its progression in mice [INCPMPM-16068]

ABSTRACT: Huntington’s disease (HD) is an incurable inherited disorder caused by repeat expansion in the huntingtin gene (Htt). The mutant protein causes neuronal degeneration leading to severe motor and psychological abnormalities. Selective downregulation of the mutant Htt by targeting Spt4/Spt5 or the Spt5-PolII transcription elongation complexes was proposed as a potential therapy. We report the identification of SPI-24 and SPI-77 small molecule inhibitors of Spt5-PolII that selectively lower mutant Htt. In the BACHD mouse model of HD, direct delivery to the striatum, subcutaneous injection and oral administration of these inhibitors diminished mutant Htt levels, ameliorated mitochondrial dysfunction and restored BDNF expression. Prolonged treatment attenuated motor and anxious-like phenotypes of HD mice and delayed disease deterioration. SPI-24 long-term treatment had no side-effects or global changes in gene expression. Mechanistically, SPIs reduce Spt5 and PolII occupancies of mutant Htt. Thus, SPIs can be an effective therapeutic strategy for HD.

ORGANISM(S): Mus musculus

PROVIDER: GSE225788 | GEO | 2023/11/20

REPOSITORIES: GEO

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Selected Spt5-Pol II inhibitors effectively relieve Huntington’s disease neuropathology and slow down its progression in mice [INCPMPM-17698]

Project description:Huntington’s disease (HD) is an incurable inherited disorder caused by repeat expansion in the huntingtin gene (Htt). The mutant protein causes neuronal degeneration leading to severe motor and psychological abnormalities. Selective downregulation of the mutant Htt by targeting Spt4/Spt5 or the Spt5-PolII transcription elongation complexes was proposed as a potential therapy. We report the identification of SPI-24 and SPI-77 small molecule inhibitors of Spt5-PolII that selectively lower mutant Htt. In the BACHD mouse model of HD, direct delivery to the striatum, subcutaneous injection and oral administration of these inhibitors diminished mutant Htt levels, ameliorated mitochondrial dysfunction and restored BDNF expression. Prolonged treatment attenuated motor and anxious-like phenotypes of HD mice and delayed disease deterioration. SPI-24 long-term treatment had no side-effects or global changes in gene expression. Mechanistically, SPIs reduce Spt5 and PolII occupancies of mutant Htt. Thus, SPIs can be an effective therapeutic strategy for HD.

2023-11-20 | GSE225789 | GEO

Genome-wide view of the impact of Spt5-Pol II inhibitors (SPIs) on mRNA levels [RNA-Seq 24h]

Project description:We identified the first Spt5-Pol II inhibitors (SPIs). SPIs faithfully reproduced Spt5 knockdown effects on proximal-promoter-pausing, NF-κB activation and the expanded-repeat huntingtin gene in neuronal cells. We determined the global effect of short and long-term SPI-21 treatment by RNA-seq and compared the affected genes between the two treatments. The results revealed that temporary and constitutive Spt5-regulated genes can be distinguished by SPIs.

2019-10-01 | GSE136023 | GEO

Genome-wide view of the impact of Spt5-Pol II inhibitors (SPIs) on mRNA levels [RNA-Seq 2h]

2019-10-01 | GSE136022 | GEO

Genome-wide view of the impact of Spt5-Pol II inhibitors (SPIs) on transcription [GRO-Seq]

Project description:We identified the first Spt5-Pol II inhibitors (SPIs). SPIs faithfully reproduced Spt5 knockdown effects on proximal-promoter-pausing, NF-κB activation and the expanded-repeat huntingtin gene in neuronal cells. Using SPIs we identified Spt5 target genes that responded with profoundly diverse kinetics and a novel regulatory element of proximal-promoter-pausing. To obtain a genome-wide view of the impact of SPIs on transcription, we performed Global run-on sequencing (GRO-seq) using nuclei of HeLa cells treated with either DMSO (control) or SPI-21.

2019-10-01 | GSE136024 | GEO

Genome-wide view of the impact of Spt5-Pol II inhibitors (SPIs) on transcription [4sU-seq]

Project description:We identified the first Spt5-Pol II inhibitors (SPIs). SPIs faithfully reproduced Spt5 knockdown effects on proximal-promoter-pausing, NF-κB activation and the expanded-repeat huntingtin gene in neuronal cells. Using SPIs we identified Spt5 target genes that responded with profoundly diverse kinetics and a novel regulatory element of proximal-promoter-pausing. To validate that the effects of SPIs are at the transcriptional level, cellular RNA was metabolically labeled with 4-thio-uridine (4sU) for 2 hours in the presence of DMSO or SPI-21 in the presence or absence of TNFα. Newly synthesized labeled RNA was then purified and subjected to RNA-seq.

2019-10-01 | GSE136025 | GEO

Experimental replacement therapy counters decreased IGF-1 levels in Huntington’s disease

Project description:Huntington’s disease (HD) is a monogenetic neurodegenerative disorder caused by the expansion of a polyglutamine (polyQ) stretch in huntingtin (htt). Here we show that mutant htt reduces the transcription of insulin-like growth factor 1 (IGF-1) and leads to loss of IGF-1 in HD brains, HD mouse models and mutant htt-transgenic microglial cells. IGF-1 replacement therapy by transplantation of genetically engineered mouse neuronal precursor cells (mNPCs) in a mouse model of HD reverted the motor phenotype and countered striatal neuronal loss.

2018-10-01 | GSE19291 | GEO

Targeting H3K4 methylation as a therapeutic strategy for Huntington's disease (RNA-seq)

Project description:Transcriptional dysregulation is an early feature of Huntington's disease (HD). We observed gene-specific changes in H3K4me3 at transcriptionally repressed promoters in R6/2 mouse and human HD brain. Genome-wide analysis showed a novel chromatin signature for this mark. Reducing the levels of the H3K4 demethylase SMCX/Jarid1c in primary neurons reversed down-regulation of key neuronal genes caused by mutant Huntingtin (Htt) expression. Finally, reduction of SMCX/Jarid1c in primary neurons from BACHD mice or the single Jarid1 in a Drosophila HD model was protective. Therefore, targeting this epigenetic signature may be an effective strategy to ameliorate the consequences of HD.

2013-07-18 | GSE48962 | GEO

Targeting H3K4 methylation as a therapeutic strategy for Huntington's disease (ChIP-seq)

2013-07-18 | GSE48960 | GEO

Targeting H3K4 methylation as a therapeutic strategy for Huntington's disease (RNA-seq)

2013-07-18 | E-GEOD-48962 | biostudies-arrayexpress

A genome-wide screening in pluripotent cells identifies Mtf1 as a suppressor of mutant huntingtin toxicity

Project description:Huntington’s disease (HD) is an inherited and incurable neurodegenerative disorder caused by CAG repeat expansions in the huntingtin (HTT) gene. The resulting mutant HTT protein alters cellular physiology at multiple levels, inducing toxicity and cell death. The mechanisms directly causing toxicity are partially understood, thus precluding the development of effective therapeutic strategies. Here we identified novel suppressors of mutant HTT toxicity by performing a genome-wide screen in pluripotent stem cells, followed by hit validation both in zebrafish and mouse HD models. The candidate suppressors identified were strongly enriched for HD-associated processes. We focused on Metal regulatory transcription factor 1 (Mtf1), a transcription factor controlling metal homeostasis in the cell. Forced expression of Mtf1 counteracts cell death, oxidative stress and transcriptional alterations caused by mutant HTT in pluripotent cells. In zebrafish, Mtf1 reduces malformations and apoptosis induced by mutant HTT, while Mtf1 delivery by Adeno-Associated viral (AAV) vectors ablated motor defects observed in an HD mouse model. Our data reveal that delivery of Mtf1 might act as a novel therapeutic strategy against HD and potentially other neurodegenerative disorders.

2023-05-30 | GSE166567 | GEO

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