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

Dohee Kim, Sungsu Lim, Md Mamunul Haque, Nayeon Ryoo, Hyun Seok Hong, Hyewhon Rhim, Dong Eun Lee, Young Tae Chang, Jun Seok Lee, Eunji Cheong, Dong Jin Kim, Yun Kyung Kim

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)

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.

Original languageEnglish
Article number15231
JournalScientific reports
Volume5
DOIs
Publication statusPublished - 2015 Oct 15

Bibliographical note

Funding Information:
This work was supported by an intramural funding from Korea Institute of Science and Technology (2E25240 and 2E25473), and grant funded by Ministry of Health & Welfare, Republic of Korea 1465016897. This research was also supported by the NRF and the WISET Grant funded by the Ministry of Science, MSIP under the Program for Returners into R&D (KW-2014-PPD-0076), Cooperative Research Program for Agriculture Science & Technology Development (PJ009103) by RDA, the Korea Atomic Energy Research Institute (KAERI) grant (Grant No. 698214-14) funded by Korea government (Ministry of Science, ICT and Future Planning) and National Medical Research Council grant (NMRC/ CBRG/0015/2012).

All Science Journal Classification (ASJC) codes

  • General

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