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Cited by 51Alzheimer's disease research and treatmentsMicrotubule and mitosis dynamicsNeuroscience and Neuropharmacology Research

Regulatory mechanisms for the axonal localization of tau protein in neurons

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Iwata, Minori, Watanabe, Shoji, Yamane, Ayaka, Miyasaka, Tomohiro, Misonou, Hiroaki·2019·Molecular Biology of the Cell
DOI 10.1091/mbc.e19-03-0183PMC PMC6743362

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Abstract

Tau is a microtubule (MT)-associated protein that is thought to be localized to the axon. However, its precise localization in developing neurons and mechanisms for the axonal localization have not been fully addressed. In this study, we found that the axonal localization of tau in cultured rat hippocampal neurons mainly occur during early neuronal development. Interestingly, transient expression of human tau in very immature neurons, but not in mature neurons, mimicked the developmental localization of endogenous tau to the axon. We therefore were able to establish an experimental model, in which exogenously expressed tau can be properly localized to the axon. Using this model, we obtained a surprising finding that the axonal localization of tau did not require stable MT binding. Tau lacking the MT-binding domain (MTBD) exhibited high diffusivity but localized properly to the axon. In contrast, a dephosphorylation-mimetic mutant of the proline-rich region 2 showed reinforced MT binding and mislocalization. Our results suggest that tight binding to MTs prevents tau from entering the axon and results in mislocalization in the soma and dendrites when expressed in mature neurons. This study therefore provides a novel mechanism independent of MTBD for the axonal localization of tau.

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  • We also found that MT-binding of wild-type Tau is quite dynamic like that of MAP2C with faster recovery than the alanine mutant, and that pseudo-phosphorylation mutant with glutamate instead of alanine substitutions exhibited recovery even faster than wild-type Tau.

    “We also found that MT-binding of wild-type Tau is quite dynamic like that of MAP2C with faster recovery than the alanine mutant, and that pseudo-phosphorylation mutant with glutamate instead of alanine substitutions exhibited recovery even faster than wild-type Tau (5).”

    From Active transport by cytoplasmic dynein sustains dendritic MAP2 localization in developing neurons (2026) · cites this paper as [5]

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  • We have previously shown that most of overexpressed Tau could bind to MTs and therefore exhibited very slow recovery in FRAP, when the phosphorylation sites in the proline-rich region (PRR) of Tau were mutated to alanine to mimic dephosphorylation.

    “We have previously shown that most of overexpressed Tau could bind to MTs and therefore exhibited very slow recovery in FRAP, when the phosphorylation sites in the proline-rich region (PRR) of Tau were mutated to alanine to mimic dephosphorylation (5).”

    From Active transport by cytoplasmic dynein sustains dendritic MAP2 localization in developing neurons (2026) · cites this paper as [5]

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Cited by

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Authors
Iwata, M., Watanabe, S., Yamane, A., Miyasaka, T., & Misonou, H.
Affiliations
  • Doshisha University (JP)
  • Laboratory of Ion Channel Pathophysiology, Graduate School of Brain Science, Doshisha University, Kyotanabe-shi, Kyoto 610-0394, Japan
Corresponding author
Misonou, Hiroaki
ORCID
Venue
Molecular Biology of the Cell
Publisher
American Society for Cell Biology (ASCB)
Published
2019-09-01
Volume
30
Issue
19
Pages
2441-2457
ISSN
  • 1059-1524 (ISSN-L)
  • 1939-4586
DOI
10.1091/mbc.e19-03-0183
PMC
PMC6743362
OpenAlex
W2964668464
Cited by
51
References
4
Citations by year
2026: 6 · 2025: 10 · 2024: 8 · 2023: 5 · 2022: 10 · 2021: 6 · 2020: 4 · 2019: 2
FWCI
3.77
Type
journal article
Language
en
Open access
Locations
  • Molecular Biology of the Cell (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
  • Ministry of Education, Culture, Sports, Science and Technology (26117004)
  • Mitsubishi Foundation
  • Japan Society for the Promotion of Science (16K07071, 16K07006, 26640030, S1201009, 26117004)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
tau protein, axonal localization, microtubule binding, microtubule-binding domain, neuronal development, hippocampal neurons, tau phosphorylation, protein mislocalization
MeSH terms
Animals, Axons, Dendrites, Female, Hippocampus, Male, Mice, Transgenic, Microtubules, Neurons, tau Proteins, Rats, Sprague-Dawley, Mice, Knockout, Mice, Rats, Primary Cell Culture

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