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    Pseudohyperphosphorylation has differential effects on polymerization and function of tau isoforms

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    Combs_ACS_2011.pdf (4.462Mb)
    Issue Date
    2011-11-08
    Author
    Combs, Benjamin
    Voss, Kellen R.
    Gamblin, Truman Chris
    Publisher
    ACS
    Type
    Article
    Article Version
    Scholarly/refereed, author accepted manuscript
    Rights
    Copyright © 2011 American Chemical Society
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    Abstract
    The microtubule-associated protein tau exists as six isoforms created through the splicing of the second, third, and tenth exons. The isoforms are classified by their number of N-terminal exons (0N, 1N or 2N) and by their number of microtubule-binding repeat regions (3R or 4R). Hyperphosphorylated isoforms accumulate in insoluble aggregates in Alzheimer’s disease and other tauopathies. These neurodegenerative diseases can be categorized based on the isoform content of the aggregates they contain. Hyperphosphorylated tau has the general characteristics of an upward electrophoretic shift, decreased microtubule binding, and an association with aggregation. Previously we have shown that a combination of seven pseudophosphorylation mutations at sites phosphorylated by GSK-3β, referred to as 7-Phos, induced several of these characteristics in full-length 2N4R tau and led to the formation of fewer but longer filaments. We sought to determine whether the same phosphorylation pattern could cause differential effects in the other tau isoforms, possibly through varied conformational effects. Using in vitro techniques, we examined the electrophoretic mobility, aggregation properties and microtubule stabilization of all isoforms and their pseudophosphorylated counterparts. We found that pseudophosphorylation affected each isoform, but in several cases certain isoforms were affected more than others. These results suggest that hyperphosphorylation of tau isoforms could play a major role in determining the isoform composition of tau aggregates in disease.
    URI
    http://hdl.handle.net/1808/23711
    DOI
    https://doi.org/10.1021/bi2010569
    Collections
    • Molecular Biosciences Scholarly Works [581]
    Citation
    Combs, B., Voss, K. R., & Gamblin, T. C. (2011). Pseudohyperphosphorylation has differential effects on polymerization and function of tau isoforms. Biochemistry, 50(44), 9446–9456. http://doi.org/10.1021/bi2010569

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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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