Alzheimer's Disease-like Paired Helical Filament Assembly from Truncated Tau Protein Is Independent of Disulfide Crosslinking

JOURNAL OF MOLECULAR BIOLOGY

卷:429

Article

Al-Hilaly, Youssra K.^1,2  Pollack, Saskia J.¹  Vadukul, Devkee M.¹  Citossi, Francesca¹  Rickard, Janet E.³  Simpson, Michael⁴  Storey, John M. D.^4,5  Harrington, Charles R.^3,5  Wischik, Claude M.^3,5  Serpell, Louise C.¹ 

[1] Univ Sussex, Sch Life Sci, Dementia Res Grp, Falmer BN1 9QG, E Sussex, England

[2] Al Mustansiriyah Univ, Chem Dept, Coll Sci, Baghdad, Iraq

[3] Univ Aberdeen, Inst Med Sci, Aberdeen AB25 2ZP, Scotland

[4] Univ Aberdeen, Dept Chem, Aberdeen AB24 3UE, Scotland

[5] TauRx Therapeut Ltd, Aberdeen AB25 2ZP, Scotland

关键词: Alzheimer's disease;    tau;    neurofibrillary tangles;    paired helical filaments;    disulfide;   

DOI  :  10.1016/j.jmb.2017.09.007

来源: Elsevier

【 摘 要 】

Alzheimer's disease is characterized by the self-assembly of tau and amyloid beta 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 fiber diffraction, we have characterized the structure of the fibrils formed from truncated tau for the first time. To explore the contribution of disulfide 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 disulfide bond formation inhibits filament assembly and that the C322A variant rapidly forms long and highly ordered PHFs. Crown Copyright (C) 2017 Published by Elsevier Ltd.

【 授权许可】

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