Publication Details

Shammas, S. L., Garcia, G. A., Kumar, S., Kjaergaard, M., Horrocks, M. H., Shivji, N., Mandelkow, E., Knowles, T. P. J., Mandelkow, E. & Klenerman, D. (2015). A mechanistic model of tau amyloid aggregation based on direct observation of oligomers. Nature Communications, 6 (April), 7025-1 - 7025-10.


Protein aggregation plays a key role in neurodegenerative disease, giving rise to small oligomers that may become cytotoxic to cells. The fundamental microscopic reactions taking place during aggregation, and their rate constants, have been difficult to determine due to lack of suitable methods to identify and follow the low concentration of oligomers over time. Here we use single-molecule fluorescence to study the aggregation of the repeat domain of tau (K18), and two mutant forms linked with familial frontotemporal dementia, the deletion mutant ΔK280 and the point mutant P301L. Our kinetic analysis reveals that aggregation proceeds via monomeric assembly into small oligomers, and a subsequent slow structural conversion step before fibril formation. Using this approach, we have been able to quantitatively determine how these mutations alter the aggregation energy landscape.



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