Title
Alzheimer’s Disease-like Paired Helical Filament Assembly from Truncated Tau Protein Is Independent of Disulfide Crosslinking
Author
Youssra K. Al-Hilaly, Saskia J. Pollack, Devkee M. Vadukul, Francesca Citossi, Janet E. Rickard, Michael Simpson, John M.D. Storey, Charles R. Harrington, Claude M. Wischik, Louise C.Serpell
Year
2017
Journal
Journal of Molecular Biology
Abstract
Alzheimer's disease is characterized by the self-assembly of tau and amyloid βproteins 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 bondformation inhibits filament assembly and that the C322A variant rapidly forms long and highly ordered PHFs.
Instrument
J-715
Keywords
Circular dichroism, Secondary structure, Aggregation, Biochemistry