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Dihydropyrimidine-thiones and clioquinol synergize to target b-amyloid cellular pathologies through a metal-dependent mechanism

ABSTRACT: DHPM-thiones rescue Ab-mediated toxicity in a metal-dependent manner that strongly synergizes with clioquinol, a known metal-binding and cytoprotective compound. RNA-seq experiments reveal a modest, yet specific effect on metal-responsive genes that do not change with the inactive control compound.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE99884 | GEO | 2017/07/18

SECONDARY ACCESSION(S): PRJNA389824

REPOSITORIES: GEO

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Dihydropyrimidine-Thiones and Clioquinol Synergize To Target β-Amyloid Cellular Pathologies through a Metal-Dependent Mechanism.

Project description:The lack of therapies for neurodegenerative diseases arises from our incomplete understanding of their underlying cellular toxicities and the limited number of predictive model systems. It is critical that we develop approaches to identify novel targets and lead compounds. Here, a phenotypic screen of yeast proteinopathy models identified dihydropyrimidine-thiones (DHPM-thiones) that selectively rescued the toxicity caused by β-amyloid (Aβ), the peptide implicated in Alzheimer's disease. Rescue of Aβ toxicity by DHPM-thiones occurred through a metal-dependent mechanism of action. The bioactivity was distinct, however, from that of the 8-hydroxyquinoline clioquinol (CQ). These structurally dissimilar compounds strongly synergized at concentrations otherwise not competent to reduce toxicity. Cotreatment ameliorated Aβ toxicity by reducing Aβ levels and restoring functional vesicle trafficking. Notably, these low doses significantly reduced deleterious off-target effects caused by CQ on mitochondria at higher concentrations. Both single and combinatorial treatments also reduced death of neurons expressing Aβ in a nematode, indicating that DHPM-thiones target a conserved protective mechanism. Furthermore, this conserved activity suggests that expression of the Aβ peptide causes similar cellular pathologies from yeast to neurons. Our identification of a new cytoprotective scaffold that requires metal-binding underscores the critical role of metal phenomenology in mediating Aβ toxicity. Additionally, our findings demonstrate the valuable potential of synergistic compounds to enhance on-target activities, while mitigating deleterious off-target effects. The identification and prosecution of synergistic compounds could prove useful for developing AD therapeutics where combination therapies may be required to antagonize diverse pathologies.

| S-EPMC5705239 | biostudies-literature

SH-SY5Y cells: DMSO vs. clioquinol

Project description:Transcriptional profiling of human SH-SY5Y neuroblastoma cells comparing DMSO-treated control cells with those treated with 50 microM clioquinol (CQ) for 24 h.

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SH-SY5Y cells: DMSO vs. clioquinol

Project description:Transcriptional profiling of human SH-SY5Y neuroblastoma cells comparing DMSO-treated control cells with those treated with 50 microM clioquinol (CQ) for 24 h. Two-condition experiment, DMSO vs. CQ . Biological replicates: 1DMSO, 1 CQ. One replicate per array.

2012-10-01 | E-GEOD-32173 | biostudies-arrayexpress

Clioquinol promotes the degradation of metal-dependent amyloid-? (A?) oligomers to restore endocytosis and ameliorate A? toxicity.

Project description:Alzheimer's disease (AD) is a common, progressive neurodegenerative disorder without effective disease-modifying therapies. The accumulation of amyloid-? peptide (A?) is associated with AD. However, identifying new compounds that antagonize the underlying cellular pathologies caused by A? has been hindered by a lack of cellular models amenable to high-throughput chemical screening. To address this gap, we use a robust and scalable yeast model of A? toxicity where the A? peptide transits through the secretory and endocytic compartments as it does in neurons. The pathogenic A? 1-42 peptide forms more oligomers and is more toxic than A? 1-40 and genome-wide genetic screens identified genes that are known risk factors for AD. Here, we report an unbiased screen of ?140,000 compounds for rescue of A? toxicity. Of ?30 hits, several were 8-hydroxyquinolines (8-OHQs). Clioquinol (CQ), an 8-OHQ previously reported to reduce A? burden, restore metal homeostasis, and improve cognition in mouse AD models, was also effective and rescued the toxicity of A? secreted from glutamatergic neurons in Caenorhabditis elegans. In yeast, CQ dramatically reduced A? peptide levels in a copper-dependent manner by increasing degradation, ultimately restoring endocytic function. This mirrored its effects on copper-dependent oligomer formation in vitro, which was also reversed by CQ. This unbiased screen indicates that copper-dependent A? oligomer formation contributes to A? toxicity within the secretory/endosomal pathways where it can be targeted with selective metal binding compounds. Establishing the ability of the A? yeast model to identify disease-relevant compounds supports its further exploitation as a validated early discovery platform.

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METAL RUST

Project description:METAL RUST Metagenome

| PRJNA347281 | ENA

Expression data of Saccharomyces cerevisiae treated with clioquinol

Project description:Clioquinol (CQ or iodochlorhydroxyquin, 5-chloro-7-iodo-8-hydroxyquinoline) is a hydrophobic chelator of copper, zinc, and iron. It was extensively used as an antibiotic for the treatment of diarrhea and skin infection in the mid-1900s, but then withdrawn because it was reported to be associated with subacute myelo-optic neuropathy (SMON) in Japan. Interest in this drug was recently revived as it was shown that CQ specifically kills cancer cells and significantly decreases Aβ level. Nevertheless, the underlying mechanisms of CQ’s drug effects and side effects are still unclear. We used yeast, Saccharomyces cerevisiae, as a model to study how CQ affects molecular and cellular functions. Genechip analysis was utilized to examine the effect of CQ on gene expression at the genomic level.

2010-05-21 | GSE17257 | GEO

Expression data of Saccharomyces cerevisiae treated with clioquinol

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2010-06-08 | E-GEOD-17257 | biostudies-arrayexpress

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Project description:Transcriptional profile of stress in fission yeast (S. pombe) cells. Five different types of stress were employed on wild type and mutant cells (sty1 and atf1 knock-out cells). The 5 stresses were heat, and four types of compound: heavy metal, oxidation, alkylation and osmosis.

2004-10-31 | E-MEXP-29 | biostudies-arrayexpress

Multi-dimensional histone modifications for coordinated regulation of gene expression under hypoxia or clioquinol (CQ) treatment.

Project description:Clioquinol (CQ) has been identified as a hypoxic mimicker to activate hypoxia-inducible factor-1α (HIF-1α) by inhibiting HIF-1a specific asparaginyl hypoxylase (Factor inhibiting HIF-1, FIH-1). We previously showed that hypoxia coordinately regulate induction or repression of hypoxia-responsive genes by altering different types of methylations (H3K4me3, H3K9me3, and H3K27me3) at gene level. Here, we investigated CQ-mediated regulation of the three histone methylations and whether CQ had a similar effect on histone methylation and transcription of target genes under hypoxia.

2022-05-25 | GSE176379 | GEO

Multi-dimensional histone modifications for coordinated regulation of gene expression under hypoxia or clioquinol (CQ) treatment [gene expression]

Project description:Clioquinol (CQ) has been identified as a hypoxic mimicker to activate hypoxia-inducible factor-1α (HIF-1α) by inhibiting HIF-1a specific asparaginyl hypoxylase (Factor inhibiting HIF-1, FIH-1). We previously showed that hypoxia coordinately regulate induction or repression of hypoxia-responsive genes by altering different types of methylations (H3K4me3, H3K9me3, and H3K27me3) at gene level. Here, we investigated CQ-mediated regulation of the expression of hypoxia-responsive genes and whether CQ had a similar effect on histone methylation and transcription of target genes under hypoxia.

2022-05-25 | GSE176557 | GEO

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