1-s2.0-S0022283618305606-main.pdf (11.5 MB)
Cysteine-independent inhibition of alzheimer's disease-like paired helical filament assembly by leuco-methylthioninium (LMT)
journal contribution
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 SerpellAlzheimer'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 BiologyISSN
0022-2836Publisher
ElsevierExternal DOI
Issue
21Volume
430Page range
4119-4131Department affiliated with
- Biochemistry Publications
Research groups affiliated with
- Dementia Research Group Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2018-08-31First Open Access (FOA) Date
2018-08-31First Compliant Deposit (FCD) Date
2018-08-30Usage metrics
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