Cited by 377Alzheimer's disease research and treatmentsParkinson's Disease Mechanisms and TreatmentsNeuroinflammation and Neurodegeneration Mechanisms

α-Synuclein Binds to Tau and Stimulates the Protein Kinase A-catalyzed Tau Phosphorylation of Serine Residues 262 and 356

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Jensen, Poul Henning, Hager, Henrik, Nielsen, Morten S., Højrup, Peter, Gliemann, Jørgen, Jakes, Ross·1999·Journal of Biological Chemistry

Abstract

alpha-Synuclein has been implicated in the pathogenesis of several neurodegenerative disorders based on the direct linking of missense mutations in alpha-synuclein to autosomal dominant Parkinson's disease and its presence in Lewy-like lesions. To gain insight into alpha-synuclein functions, we have investigated whether it binds neuronal proteins and modulates their functional state. The microtubule-associated protein tau was identified as a ligand by alpha-synuclein affinity chromatography of human brain cytosol. Direct binding assays using (125)I-labeled human tau40 demonstrated a reversible binding with a IC(50) about 50 pM. The interacting domains were localized to the C terminus of alpha-synuclein and the microtubule binding region of tau as determined by protein fragmentation and the use of recombinant peptides. High concentrations of tubulin inhibited the binding between tau and alpha-synuclein. Functionally, alpha-synuclein stimulated the protein kinase A-catalyzed phosphorylation of tau serine residues 262 and 356 as determined using a phospho-epitope-specific antibody. We propose that alpha-synuclein modulates the phosphorylation of soluble axonal tau and thereby indirectly affects the stability of axonal microtubules.

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  1. Ueda, K., Fukushima, H., Masliah, E., Xia, Y., Iwai, A., Yoshimoto, M., Otero, D. A., Kondo, J., Ihara, Y., and Saitoh, T. (1993) Proc. Natl. Acad. Sci.
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Authors
Jensen, P. H., Hager, H., Nielsen, M. S., Højrup, P., Gliemann, J., & Jakes, R.
Affiliations
  • Aarhus University (DK)
  • University of Southern Denmark (DK)
  • MRC Laboratory of Molecular Biology (GB)
Corresponding author
Jensen, Poul Henning
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
1999-09
Volume
274
Issue
36
Pages
25481-25489
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2016473759
Cited by
377
References
48
Citations by year
2026: 7 · 2025: 10 · 2024: 11 · 2023: 8 · 2022: 13 · 2021: 21 · 2020: 17 · 2019: 15 · 2018: 16 · 2017: 18 · 2016: 12 · 2015: 9 · 2014: 15 · 2013: 17 · 2012: 15
FWCI
10.41
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion, other-oa)
Funders
Michaelsen Fonden
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
alpha-synuclein, tau protein, protein-protein binding, protein kinase A, tau phosphorylation, Parkinson's disease, Lewy bodies, microtubule binding, neurodegenerative diseases
MeSH terms
Axons, Escherichia coli, Humans, Nerve Tissue Proteins, Neurons, Phosphoproteins, Phosphorylation, Serine, Signal Transduction, tau Proteins, Cyclic AMP-Dependent Protein Kinases, Synucleins, alpha-Synuclein

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