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Sci Rep. 2015 Oct 15;5:15231. doi: 10.1038/srep15231.

Identification of disulfide cross-linked tau dimer responsible for tau propagation.

Author information

1
Korea Institute of Science and Technology (KIST), Brain Science Institute, Center for neuro-medicine, Seoul 136-791, South Korea.
2
Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, South Korea.
3
Biological Chemistry, University of Science and Technology (UST), Daejon 305-333, South Korea.
4
Korea Institute of Science and Technology (KIST), Brain Science Institute, Center for Neuroscience, Seoul 136-791, South Korea.
5
Medifron-DBT Inc., Ansan, 425-839, South Korea.
6
Department of Neuroscience, University of Science and Technology (UST), Daejon 305-333, South Korea.
7
Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup 580-185, South Korea.
8
Department of Chemistry &Med Chem Program, National University of Singapore, 3 Science Drive 2, 117543 Singapore (Singapore).
9
Singapore BioImaging Consortium, Agency for Science, Technology and Research, 11 Biopolis Way, 138667 Singapore (Singapore).
10
Korea Institute of Science and Technology (KIST), Molecular Recognition Research Center, Seoul 136-791, South Korea.

Abstract

Recent evidence suggests that tau aggregates are not only neurotoxic, but also propagate in neurons acting as a seed for native tau aggregation. Prion-like tau transmission is now considered as an important pathogenic mechanism driving the progression of tau pathology in the brain. However, prion-like tau species have not been clearly characterized. To identify infectious tau conformers, here we prepared diverse tau aggregates and evaluated the effect on inducing intracellular tau-aggregation. Among tested, tau dimer containing P301L-mutation is identified as the most infectious form to induce tau pathology. Biochemical analysis reveals that P301L-tau dimer is covalently cross-linked with a disulfide bond. The relatively small and covalently cross-linked tau dimer induced tau pathology efficiently in primary neurons and also in tau-transgenic mice. So far, the importance of tau disulfide cross-linking has been overlooked in the study of tau pathology. Here our results suggested that tau disulfide cross-linking might play critical role in tau propagation by producing structurally stable and small tau conformers.

PMID:
26470054
PMCID:
PMC4606741
DOI:
10.1038/srep15231
[Indexed for MEDLINE]
Free PMC Article

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