Identification of disulfide cross-linked tau dimer responsible for tau propagation

Sci Rep. 2015 Oct 15;5:15231. doi: 10.1038/srep15231.

Abstract

Recent evidence suggests that tau aggregates are not only neurotoxic, but also propagate in neurons acting as a seed for native tau aggregation. Prion-like tau transmission is now considered as an important pathogenic mechanism driving the progression of tau pathology in the brain. However, prion-like tau species have not been clearly characterized. To identify infectious tau conformers, here we prepared diverse tau aggregates and evaluated the effect on inducing intracellular tau-aggregation. Among tested, tau dimer containing P301L-mutation is identified as the most infectious form to induce tau pathology. Biochemical analysis reveals that P301L-tau dimer is covalently cross-linked with a disulfide bond. The relatively small and covalently cross-linked tau dimer induced tau pathology efficiently in primary neurons and also in tau-transgenic mice. So far, the importance of tau disulfide cross-linking has been overlooked in the study of tau pathology. Here our results suggested that tau disulfide cross-linking might play critical role in tau propagation by producing structurally stable and small tau conformers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism
  • Brain / pathology
  • Cells, Cultured
  • Dimerization
  • Disulfides / chemistry*
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Transgenic
  • Microscopy, Electron, Transmission
  • Microscopy, Fluorescence
  • Mutagenesis
  • Neurons / cytology
  • Neurons / metabolism
  • Rats
  • tau Proteins / chemistry
  • tau Proteins / genetics
  • tau Proteins / metabolism*

Substances

  • Disulfides
  • tau Proteins