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

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posted on 2023-06-09, 14:52 authored by Youssra Al-Hilaly, Saskia Pollack, Janet E Rickard, Michael Simpson, Ana Raulin, Thomas Baddeley, Pascale Schellenberger, John M D Storey, Charles R Harrington, Claude M Wischik, Louise SerpellLouise Serpell
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.

Funding

G1261; Taurx

History

Publication status

  • Published

File Version

  • Accepted version

Journal

Journal of Molecular Biology

ISSN

0022-2836

Publisher

Elsevier

Issue

21

Volume

430

Page range

4119-4131

Department affiliated with

  • Biochemistry Publications

Research groups affiliated with

  • Dementia Research Group Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2018-08-31

First Open Access (FOA) Date

2018-08-31

First Compliant Deposit (FCD) Date

2018-08-30

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