Show simple item record

dc.rights.licenseACS AuthorChoice License
dc.rights.licenseOpen Access
dc.contributor.authorDespres, C.
dc.contributor.authorDi, J.
dc.contributor.authorCantrelle, F.X.
dc.contributor.authorLi, Z.
dc.contributor.authorHuvent, I.
dc.contributor.authorChambraud, B.
dc.contributor.authorZhao, J.
dc.contributor.authorChen, J.
dc.contributor.authorChen, S.
dc.contributor.authorLippens, G.
dc.contributor.authorZhang, F.
dc.contributor.authorLinhardt, Robert J.
dc.contributor.authorWang, C.
dc.contributor.authorKlärner, F.G.
dc.contributor.authorSchrader, T.
dc.contributor.authorLandrieu, I.
dc.contributor.authorBitan, G.
dc.contributor.authorSmet-Nocca, C.
dc.date2019
dc.date.accessioned2022-06-23T04:28:40Z
dc.date.available2022-06-23T04:28:40Z
dc.date.issued2019-06-21
dc.identifier.citationMajor differences between the self-assembly and seeding behavior of heparin-induced- and in-vitro-phosphorylated tau and their modulation by potential inhibitors, C. Despres, J. Di, F.-X. Cantrelle, Z. Li,; I. Huvent, B. Chambraud, J. Zhao, J. Chen, S. Chen, G. Lippens, F. Zhang, R. J. Linhardt, C. Wang, F.-G. Klärner, T. Schrader, I. Landrieu, G. Bitan, C. Smet-Nocca, ACS Chemical Biology, 14, 1363−1379, 2019.
dc.identifier.issn15548937
dc.identifier.issn15548929
dc.identifier.urihttps://hdl.handle.net/20.500.13015/5365
dc.identifier.urihttps://doi.org/10.1021/acschembio.9b00325
dc.descriptionACS Chemical Biology, 14, 1363−1379
dc.descriptionNote : if this item contains full text it may be a preprint, author manuscript, or a Gold OA copy that permits redistribution with a license such as CC BY. The final version is available through the publisher’s platform.
dc.description.abstractSelf-assembly of the microtubule-associated protein tau into neurotoxic oligomers, fibrils, and paired helical filaments, and cell-to-cell spreading of these pathological tau species are critical processes underlying the pathogenesis of Alzheimer’s disease and other tauopathies. Modulating the self-assembly process and inhibiting formation and spreading of such toxic species are promising strategies for therapy development. A challenge in investigating tau self-assembly in vitro is that, unlike most amyloidogenic proteins, tau does not aggregate in the absence of posttranslational modifications (PTM), aggregation inducers, or preformed seeds. The most common induction method is addition of polyanions, such as heparin; yet, this artificial system may not represent adequately tau self-assembly in vivo, which is driven by aberrant phosphorylation and other PTMs, potentially leading to in vitro data that do not reflect the behavior of tau and its interaction with modulators in vivo. To tackle these challenges, methods for in vitro phosphorylation of tau to produce aggregation-competent forms recently have been introduced (Despres et al. (2017) Proc. Natl. Acad. Sci. U.S.A., 114, 9080−9085). However, the oligomerization, seeding, and interaction with assembly modulators of the different forms of tau have not been studied to date. To address these knowledge gaps, we compared here side-by-side the self-assembly and seeding activity of heparin-induced tau with two forms of in vitro phosphorylated tau and tested how the molecular tweezer CLR01, a negatively charged compound, affected these processes. Tau was phosphorylated by incubation either with activated extracellular signal-regulated kinase 2 or with a whole rat brain extract. Seeding activity was measured using a fluorescence-resonance energy transfer-based biosensor-cell method. We also used solution-state NMR to investigate the binding sites of CLR01 on tau and how they were impacted by phosphorylation. Our systematic structure–activity relationship study demonstrates that heparin-induced tau behaves differently from in vitro phosphorylated tau. The aggregation rates of the different forms are distinct as is the intracellular localization of the induced aggregates, which resemble brain-derived tau strains suggesting that heparin-induced tau and in vitro phosphorylated tau have different conformations, properties, and activities. CLR01 inhibits aggregation and seeding of both heparin-induced and in vitro phosphorylated tau dose-dependently, although heparin induction interferes with the interaction between CLR01 and tau.
dc.description.sponsorshipNational Institute on Aging
dc.languageen_US
dc.language.isoENG
dc.publisherAmerican Chemical Society (ACS)
dc.relation.ispartofThe Linhardt Research Labs Online Collection
dc.relation.ispartofRensselaer Polytechnic Institute, Troy, NY
dc.relation.ispartofACS Chemical Biology
dc.relation.urihttps://harc.rpi.edu/
dc.subjectBiology
dc.subjectChemistry and chemical biology
dc.subjectChemical and biological engineering
dc.subjectBiomedical engineering
dc.titleMajor differences between the self-assembly and seeding behavior of heparin-induced- and in-vitro-phosphorylated tau and their modulation by potential inhibitors
dc.typeArticle
dcterms.accessRightsA full text version is available in DSpace@RPI
dcterms.isPartOfJournal
dcterms.isVersionOfhttps://doi.org/10.1021/acschembio.9b00325
dc.rights.holderIn Copyright : this Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s). https://rightsstatements.org/page/InC/1.0/
dc.creator.identifierhttps://orcid.org/0000-0003-2219-5833
dc.relation.departmentThe Linhardt Research Labs.
dc.relation.departmentThe Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies (CBIS)
rpi.description.pages1363-1379
rpi.description.volume14


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record