Tau protein assembles into isoform- and disulfide-dependent polymorphic fibrils with distinct structural properties

Yoshiaki Furukawa, Kumi Kaneko, Nobuyuki Nukina

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Tauopathies are neurodegenerative diseases in which insoluble fibrillar aggregates of a microtubule-binding protein, Tau, are abnormally accumulated. Pathological Tau fibrils often exhibit structural polymorphisms that differ among phenotypically distinct tauopathies; however, a molecular mechanism to generate polymorphic Tau fibrils remains obscure. Here, we note the formation of a disulfide bond in isoforms of full-length Tau and show that the thiol-disulfide status as well as the isoform composition determines structural and morphological properties of Tau fibrils in vitro. Mainly two regions in a Tau primary sequence are found to act as structural blocks for building a protease-resistant core of Tau fibrils. Interactions among those two blocks for building a core structure depend upon the thiol-disulfide status in each isoform of Tau, which results in the formation of polymorphic fibrils with distinct structural properties. Furthermore, we have found that more diverse structures of Tau fibrils emerge through a cross-seeded fibrillation between heterologous pairs of Tau isoforms. We thus propose that isoform- and disulfide-dependent combinatorial interactions among multiple regions in a Tau sequence endow Tau fibrils with various structures, i.e. polymorphism.

Original languageEnglish
Pages (from-to)27236-27246
Number of pages11
JournalJournal of Biological Chemistry
Volume286
Issue number31
DOIs
Publication statusPublished - 2011 Aug 5

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Tau protein assembles into isoform- and disulfide-dependent polymorphic fibrils with distinct structural properties'. Together they form a unique fingerprint.

  • Cite this