Heparin-induced tau filaments are structurally heterogeneous and differ from Alzheimer's disease filaments.
Y. Fichou, M. Vigers, A.K. Goring, N.A. Eschmann, and S. Han, Chemical Communications 54, 4573 (2018). DOI: 10.1039/C8CC01355Aa
Alzheimer's disease (AD) is characterized by the presence of tau filaments in the brain whose structure was recently solved. The formation of AD filaments is routinely modeled in vitro by mixing tau with heparin. Our study shows that heparin-induced tau filaments are markedly different from the AD filaments and are highly heterogeneous.
RNA stores tau reversibly in complex coacervates
X. Zhang, Y. Lin, N.A. Eschmann, H. Zhou, J.N. Rauch, I. Hernandez, E. Guzman, K.S. Kosik, and S. Han, PLoS Biol 15(7), e2002183 (2017). DOI:10.1371/journal.pbio.2002183
Nonmembrane-bound organelles that behave like liquid droplets are widespread among eukaryotic cells. Their dysregulation appears to be a critical step in several neurodegenerative conditions. Here, we report that tau protein, the primary constituent of Alzheimer neurofibrillary tangles, can form liquid droplets and therefore has the necessary biophysical properties to undergo liquid-liquid phase separation (LLPS) in cells. We furthermore show that the LLPS process is directly and sensitively tuned by salt concentration and temperature, implying it is modulated by both electrostatic interactions between the involved protein and nucleic acid constituents, as well as net changes in entropy. These findings suggest that the droplet state can incubate tau and predispose the protein toward the formation of insoluble fibrils.
Signature of an aggregation-prone conformation of tau
N.A. Eschmann, E.R. Georgieva, P. Ganguly, P.P. Borbat, M.D. Rappaport, Y. Akdogan, J.H. Freed, J.-E. Shea, and S. Han, Scientific Reports 7, (2017). DOI:10.1038/srep44739
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.
Protein structural and surface water rearrangement constitute major events in the earliest aggregation stages of tau
A. Pavlova, C.-Y. Cheng, M. Kinnebrew, J. Lew, F.W. Dahlquist, and S. Han, PNAS 113, E127 (2016). DOI:10.1073/pnas.1504415113
Amyloid fibril formation is a key process accompanying many neurodegenerative diseases. Oligomers formed in the early stages of aggregation have been thought to play a key role in disease effects, but their studies are challenging. We use site-specific measurements of surface water diffusion, protein segmental dynamics, and interstrand packing to track early tau protein aggregation processes in situ. Our study reveals that tau aggregation is accompanied by a dramatic structural transformation within minutes of initiating aggregation, followed by the formation of partially structured aggregation intermediates and their rearrangement into stable aggregate species with β-sheet signatures and fibrils. Our findings suggest that therapeutic intervention may focus on disrupting the earliest aggregation events occurring in solution.