Tau-tubulin kinase 1 (TTBK1), a neuron-specific tau kinase candidate, is involved in tau phosphorylation and aggregation

J Neurochem. 2006 Sep;98(5):1573-84. doi: 10.1111/j.1471-4159.2006.04059.x.

Abstract

Neurofibrillary tangles, which are major pathological hallmarks of Alzheimer's disease (AD), are composed of paired helical filaments (PHFs) containing hyperphosphorylated tau. Specific kinases regulate tau phosphorylation and are closely linked to the pathogenesis of AD. We have characterized a human tau-tubulin kinase 1 (TTBK1) gene located on chromosome 6p21.1. TTBK1 is a serine/threonine/tyrosine kinase that is conserved among species and belongs to the casein kinase 1 superfamily. It is specifically expressed in the brain, especially in the cytoplasm of cortical and hippocampal neurons. TTBK1 phosphorylates tau proteins in both a Mg2+- and a Mn2+-dependent manner. Phosphopeptide mapping and immunoblotting analysis confirmed a direct tau phosphorylation by TTBK1 at Ser198, Ser199, Ser202 and Ser422, which are also phosphorylated in PHFs. TTBK1 also induces tau aggregation in human neuronal cells in a dose-dependent manner. We conclude that TTBK1 is a neuron-specific dual kinase involved in tau phosphorylation at AD-related sites and is also associated with tau aggregation.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Chlorocebus aethiops
  • Computational Biology / methods
  • Fluorescent Antibody Technique / methods
  • Gene Expression / physiology
  • Humans
  • Immunoprecipitation / methods
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Neuroblastoma
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / physiology*
  • Sequence Alignment / methods
  • Serine / metabolism
  • Threonine / metabolism
  • Tissue Distribution
  • Transfection / methods
  • tau Proteins / metabolism*

Substances

  • tau Proteins
  • Threonine
  • Serine
  • tau-tubulin kinase
  • Protein-Serine-Threonine Kinases

Associated data

  • GENBANK/AB218664