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alpha-synuclein binds to Tau and stimulates the protein kinase A-catalyzed tau phosphorylation of serine residues 262 and 356.

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.

Pubmed ID: 10464279

Authors

  • Jensen PH
  • Hager H
  • Nielsen MS
  • Hojrup P
  • Gliemann J
  • Jakes R

Journal

The Journal of biological chemistry

Publication Data

September 3, 1999

Associated Grants

None

Mesh Terms

  • Axons
  • Cyclic AMP-Dependent Protein Kinases
  • Escherichia coli
  • Humans
  • Nerve Tissue Proteins
  • Neurons
  • Phosphoproteins
  • Phosphorylation
  • Serine
  • Signal Transduction
  • Synucleins
  • alpha-Synuclein
  • tau Proteins