Three-repeat and four-repeat tau isoforms form different oligomers

Shahpasand‐Kroner, Hedieh; Portillo, Jennifer; Lantz, Carter; Seidler, Paul M.; Sarafian, Natalie; Loo, Joseph A.; Bitan, Gal

doi:10.1002/pro.4257

Title: Three-repeat and four-repeat tau isoforms form different oligomers

Journal Article · 12 December 2021 · Protein Science

DOI: https://doi.org/10.1002/pro.4257 · OSTI ID:1976375

Shahpasand‐Kroner, Hedieh ^[1]; Portillo, Jennifer ^[2]; Lantz, Carter ^[2]; Seidler, Paul M. ^[3]; Sarafian, Natalie ^[2]; Loo, Joseph A. ^[2];

^[2]

Univ. of California, Los Angeles, CA (United States); OSTI
Univ. of California, Los Angeles, CA (United States)
Univ. of Southern California, Los Angeles, CA (United States)

Different tauopathies are characterized by the isoform-specific composition of the aggregates found in the brain and by structurally distinct tau strains. Although tau oligomers have been implicated as important neurotoxic species, little is known about how the primary structures of the six human tau isoforms affect tau oligomerization because the oligomers are metastable and difficult to analyze. To address this knowledge gap, here, we analyzed the initial oligomers formed by the six tau isoforms in the absence of posttranslational modifications or other manipulations using dot blots probed by an oligomer-specific antibody, native-PAGE/western blots, photo-induced cross-linking of unmodified proteins, mass-spectrometry, and ion-mobility spectroscopy. We found that under these conditions, three-repeat (3R) isoforms are more prone than four-repeat (4R) isoforms to form oligomers. In this study, we also tested whether known inhibitors of tau aggregation affect its oligomerization using three small molecules representing different classes of tau aggregation inhibitors, Methylene Blue (MB), the molecular tweezer CLR01, and the all-D peptide TLKIVW, for their ability to inhibit or modulate the oligomerization of the six tau isoforms. Unlike their reported inhibitory effect on tau fibrillation, the inhibitors had little or no effect on the initial oligomerization. Our study provides novel insight into the primary–quaternary structure relationship of human tau and suggests that 3R-tau oligomers may be an important target for future development of compounds targeting pathological tau assemblies.

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Research Organization:: Univ. of California, Los Angeles, CA (United States)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC)

Grant/Contract Number:: FC02-02ER63421

OSTI ID:: 1976375

Journal Information:: Protein Science, Journal Name: Protein Science Journal Issue: 3 Vol. 31; ISSN 0961-8368

Publisher:: WileyCopyright Statement

Country of Publication:: United States

Language:: English

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