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Hyperphosphorylation induces self-assembly of τ into tangles of paired helical filaments/straight filaments

Alonso, Alejandra del C., Zaidi, Tanweer, Novak, Michal, Grundke-Iqbal, Inge, Iqbal, Khalid·2001·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.121119298
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Abstract

The microtubule-associated protein τ is a family of six isoforms that becomes abnormally hyperphosphorylated and accumulates in the form of paired helical filaments (PHF) in the brains of patients with Alzheimer's disease (AD) and patients with several other tauopathies. Here, we show that the abnormally hyperphosphorylated τ from AD brain cytosol (AD P-τ) self-aggregates into PHF-like structures on incubation at pH 6.9 under reducing conditions at 35°C during 90 min. In vitro dephosphorylation, but not deglycosylation, of AD P-τ inhibits its self-association into PHF. Furthermore, hyperphosphorylation induces self-assembly of each of the six τ isoforms into tangles of PHF and straight filaments, and the microtubule binding domains/repeats region in the absence of the rest of the molecule can also self-assemble into PHF. Thus, it appears that τ self-assembles by association of the microtubule binding domains/repeats and that the abnormal hyperphosphorylation promotes the self-assembly of τ into tangles of PHF and straight filaments by neutralizing the inhibitory basic charges of the flanking regions.

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  • Hyperphosphorylation of tau induces conformational changes that promote protein aggregation.

    “Hyperphosphorylation of tau induces conformational changes that promote protein aggregation (Alonso et al., 2001).”

    From Cholesterol 25-hydroxylase mediates neuroinflammation and neurodegeneration in a mouse model of tauopathy (2024) · cites this paper as Alonso et al., 2001

    The Results show that hyperphosphorylation promotes tau self-assembly into filaments and tangles. The Discussion proposes that phosphorylation neutralizes inhibitory charges, allowing assembly, but does not establish the claimed conformational changes as the mechanism. (LLM, conf=0.86)

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Metadata

Authors
Alonso, A. D. C., Zaidi, T., Novak, M., Grundke-Iqbal, I., & Iqbal, K.
Affiliations
New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314; and Institute of Neuroimmunology, Slovak Academy of Sciences, Dubrovdka cesta 9, 842 46 Bratislava, Slovak Republic
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2001-05-29
Volume
98
Issue
12
Pages
6923-6928
ISSN
  • 0027-8424
  • 1091-6490
DOI
10.1073/pnas.121119298
Cited by
827
References
7
Language
en

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