Signature of an aggregation-prone conformation of tau.

TitleSignature of an aggregation-prone conformation of tau.
Publication TypeJournal Article
Year of Publication2017
AuthorsEschmann NA, Georgieva ER, Ganguly P, Borbat PP, Rappaport MD, Akdogan Y, Freed JH, Shea J-E, Han S
JournalSci Rep
Date Published2017 Mar 17

The self-assembly of the microtubule associated tau protein into fibrillar cell inclusions is linked to a number of devastating neurodegenerative disorders collectively known as tauopathies. The mechanism by which tau self-assembles into pathological entities is a matter of much debate, largely due to the lack of direct experimental insights into the earliest stages of aggregation. We present pulsed double electron-electron resonance measurements of two key fibril-forming regions of tau, PHF6 and PHF6*, in transient as aggregation happens. By monitoring the end-to-end distance distribution of these segments as a function of aggregation time, we show that the PHF6((*)) regions dramatically extend to distances commensurate with extended β-strand structures within the earliest stages of aggregation, well before fibril formation. Combined with simulations, our experiments show that the extended β-strand conformational state of PHF6((*)) is readily populated under aggregating conditions, constituting a defining signature of aggregation-prone tau, and as such, a possible target for therapeutic interventions.

Alternate JournalSci Rep
PubMed ID28303942
PubMed Central IDPMC5356194
Grant ListP41 GM103521 / GM / NIGMS NIH HHS / United States
R21 EB022731 / EB / NIBIB NIH HHS / United States
S10 RR028992 / RR / NCRR NIH HHS / United States