Signature of an Aggregation-Prone Conformation of Tau Elucidated by Pulse Dipolar ESR

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 made pulsed Dipolar ESR measurements of two key fibril-forming regions of tau, PHF6 and PHF6*,during the course of the aggregation. By monitoring the end-to-end distance distribution of these segments as a function of aggregation time, we showed 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.

Funding:R21EB022731 (to SH), NSF MCB 1158577 (to JS), P41GM103521 (to JHF).

Publication: Eschmann NA, Georgieva ER, Ganguly P, Borbat PP,. Rappaport MD, Akdogan Y, Freed JH,. Shea J-E, and Han S. Sci. Rep. 7, 44739 (2017); PMCID: PMC5356194.