Cysteine-independent inhibition of Alzheimer's disease-like paired helical filament assembly by leuco-methylthioninium (LMT)

Youssra K. Al-Hilaly, Saskia J. Pollack, Janet E. Rickard, Michael Simpson, Ana-C Raulin, Thomas Baddeley, Pascale Schellenberger, John M. D. Storey, Charles R. Harrington, Claude M. Wischik (Corresponding Author), Louise C. Serpell (Corresponding Author)

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Abstract

Alzheimer's disease (AD) is a tauopathy characterised by pathological fibrillisation of tau protein to form the paired helical filaments (PHFs) which constitute neurofibrillary tangles. The methylthioninium (MT) moiety reverses the proteolytic stability of the PHF core and is in clinical development for treatment of AD in a stable reduced form as leuco-MT (LMT). It has been hypothesised that MT acts via oxidation of cysteine residues which is incompatible with activity in the predominantly reducing environment of living cells. We have shown recently that the PHF-core tau unit assembles spontaneously in vitro to form PHF-like filaments. Here we describe studies using circular dichroism, SDS-polyacrylamide gel electrophoresis, transmission electron microscopy and site-directed mutagenesis to elucidate the mechanism of action of the MT moiety. We show that MT inhibitory activity is optimal in reducing conditions, that the active moiety is the reduced LMT form of the molecule, and that its mechanism of action is cysteine-independent.
Original languageEnglish
Pages (from-to)4119-4131
Number of pages13
JournalJournal of Molecular Biology
Volume430
Issue number21
Early online date16 Aug 2018
DOIs
Publication statusPublished - 19 Oct 2018

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Keywords

  • Tau
  • Methylthioninium
  • Hydromethylthionine
  • Neurofibrillary tangles
  • Circular dichroism
  • Electron microscopy

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