Al-Hilaly, Youssra K, Pollack, Saskia J, Vadukul, Devkee, Citossi, Francesca, Rickard, Janet E, Simpson, Michael, Storey, John M D, Harrington, Charles R, Wischik, Claude M and Serpell, Louise C (2017) Alzheimer's disease-like paired helical filament assembly from truncated tau protein is independent of disulphide cross-linking. Journal of Molecular Biology, 429 (4). pp. 3650-3665. ISSN 0022-2836

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Abstract

Abstract Alzheimer's disease is characterised by the self-assembly of tau and amyloid β proteins into oligomers and fibrils. Tau protein assembles into paired helical filaments (PHFs) that constitute the neurofibrillary tangles observed in neuronal cell bodies in individuals with Alzheimer's disease. The mechanism of initiation of tau assembly into {PHFs} is not well understood. Here we report that a truncated 95-amino acid tau fragment (corresponding to residues 297-391 of full-length tau) assembles into PHF-like fibrils in vitro without the need for other additives to initiate or template the process. Using electron microscopy, circular dichroism and X-ray fibre diffraction, we have characterised the structure of the fibrils formed from truncated tau for the first time. To explore the contribution of disulphide formation to fibril formation, we have compared the assembly of tau(297-391) under reduced and non-reducing conditions and for truncated tau carrying a {C322A} substitution. We show that disulphide bond formation inhibits assembly and that the {C322A} variant rapidly forms long and highly ordered PHFs.

Item Type:	Article
Keywords:	disulphide
Schools and Departments:	School of Life Sciences > Biochemistry
Subjects:	Q Science > QD Chemistry > QD0241 Organic chemistry > QD0415 Biochemistry
Depositing User:	Youssra Al-Hilaly
Date Deposited:	20 Sep 2017 10:00
Last Modified:	02 Jul 2019 14:04
URI:	http://sro.sussex.ac.uk/id/eprint/70243

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