Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

A novel small molecule screening platform for disrupting toxic tau oligomers in cells

Chih Hung Lo, Colin Kin-Wye Lim, Zhipeng Ding, Sanjula Wickramasinghe, Anthony R. Braun, Elizabeth Rhoades, David D. Thomas, Jonathan N. Sachs
doi: https://doi.org/10.1101/510412
Chih Hung Lo
1Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Colin Kin-Wye Lim
1Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Zhipeng Ding
1Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sanjula Wickramasinghe
2Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Anthony R. Braun
1Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Elizabeth Rhoades
2Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David D. Thomas
3Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455
4Photonic Pharma LLC, Minneapolis, MN 55410
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jonathan N. Sachs
1Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: jnsachs@umn.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Preview PDF
Loading

Abstract

Tauopathies, including Alzheimer’s disease, are a group of neurodegenerative disorders characterized by pathological aggregation of the microtubule binding protein tau. Recent studies suggest that toxic tau oligomers, which are soluble and distinct from insoluble beta-sheet fibrils, are central players in neuronal cell death. To exploit this new therapeutic window, we engineered two first-in-class FRET based biosensors that monitor tau conformations in cells. Because this new technology platform operates in cells, it enables high-throughput screening of small molecules that target tau oligomers while avoiding the uncertainties of idiosyncratic in vitro preparations of tau assemblies from purified protein. We found a small molecule, MK-886, that disrupts tau oligomers and reduces tau-induced cell cytotoxicity with nanomolar potency. Using SPR and an advanced single-molecule FRET technique, we show that MK-886 directly binds to tau and specifically perturbs the folding of tau monomer in the proline-rich and microtubule-binding regions. Furthermore, we show that MK-886 accelerates the tau aggregation lag phase using a thioflavin-T assay, implying that the compound stabilizes a non-toxic, on-pathway oligomer. The technology described here should generalize to the study and targeting of conformational ensembles within the aggregation pathways of most intrinsically disordered proteins.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Back to top
PreviousNext
Posted January 03, 2019.
Download PDF
Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
A novel small molecule screening platform for disrupting toxic tau oligomers in cells
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
A novel small molecule screening platform for disrupting toxic tau oligomers in cells
Chih Hung Lo, Colin Kin-Wye Lim, Zhipeng Ding, Sanjula Wickramasinghe, Anthony R. Braun, Elizabeth Rhoades, David D. Thomas, Jonathan N. Sachs
bioRxiv 510412; doi: https://doi.org/10.1101/510412
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
A novel small molecule screening platform for disrupting toxic tau oligomers in cells
Chih Hung Lo, Colin Kin-Wye Lim, Zhipeng Ding, Sanjula Wickramasinghe, Anthony R. Braun, Elizabeth Rhoades, David D. Thomas, Jonathan N. Sachs
bioRxiv 510412; doi: https://doi.org/10.1101/510412

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Neuroscience
Subject Areas
All Articles
  • Animal Behavior and Cognition (3505)
  • Biochemistry (7346)
  • Bioengineering (5323)
  • Bioinformatics (20260)
  • Biophysics (10016)
  • Cancer Biology (7743)
  • Cell Biology (11300)
  • Clinical Trials (138)
  • Developmental Biology (6437)
  • Ecology (9951)
  • Epidemiology (2065)
  • Evolutionary Biology (13321)
  • Genetics (9361)
  • Genomics (12583)
  • Immunology (7701)
  • Microbiology (19021)
  • Molecular Biology (7441)
  • Neuroscience (41036)
  • Paleontology (300)
  • Pathology (1229)
  • Pharmacology and Toxicology (2137)
  • Physiology (3160)
  • Plant Biology (6860)
  • Scientific Communication and Education (1272)
  • Synthetic Biology (1896)
  • Systems Biology (5311)
  • Zoology (1089)