Signature of an aggregation-prone conformation of tau

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.NIH (S10 RR028992); NIH Innovator award; NIH/NIGMS (R21EB022731-- P41-GM103521), NSF (MCB 1158577); NSF MRSEC Program (DMR 1121053); Center for Scientific Computing at the UCSB CNSI (CNS-0960316); Extreme Science and Engineering Discovery Environment-XSEDE - NSF (TG-MCA05S027--ACI-1053575); University of California; Santa Barbara; University of California, Office of the Presiden