Take our Survey

Reference: Matlack KE, et al. (2014) Clioquinol promotes the degradation of metal-dependent amyloid-? (A?) oligomers to restore endocytosis and ameliorate A? toxicity. Proc Natl Acad Sci U S A 111(11):4013-8

Reference Help

Abstract


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.

Reference Type
Journal Article
Authors
Matlack KE, Tardiff DF, Narayan P, Hamamichi S, Caldwell KA, Caldwell GA, Lindquist S
Primary Lit For
Additional Lit For
Review For

Interaction Annotations


Increase the total number of rows showing on this page by using the pull-down located below the table, or use the page scroll at the table's top right to browse through the table's pages; use the arrows to the right of a column header to sort by that column; filter the table using the "Filter" box at the top of the table; click on the small "i" buttons located within a cell for an annotation to view further details about experiment type and any other genes involved in the interaction.

Interactor Interactor Type Assay Annotation Action Modification Phenotype Source Reference

Gene Ontology Annotations


Increase the total number of rows showing on this page using the pull-down located below the table, or use the page scroll at the table's top right to browse through the table's pages; use the arrows to the right of a column header to sort by that column; filter the table using the "Filter" box at the top of the table.

Gene Gene Ontology Term Qualifier Aspect Method Evidence Source Assigned On Annotation Extension Reference

Phenotype Annotations


Increase the total number of rows showing on this page using the pull-down located below the table, or use the page scroll at the table's top right to browse through the table's pages; use the arrows to the right of a column header to sort by that column; filter the table using the "Filter" box at the top of the table; click on the small "i" buttons located within a cell for an annotation to view further details.

Gene Phenotype Experiment Type Mutant Information Strain Background Chemical Details Reference

Regulation Annotations


Increase the total number of rows displayed on this page using the pull-down located below the table, or use the page scroll at the table's top right to browse through the table's pages; use the arrows to the right of a column header to sort by that column; to filter the table by a specific experiment type, type a keyword into the Filter box (for example, “microarray”); download this table as a .txt file using the Download button or click Analyze to further view and analyze the list of target genes using GO Term Finder, GO Slim Mapper, SPELL, or YeastMine.

Regulator Target Experiment Assay Construct Conditions Strain Background Reference