A mechanistic model of tau amyloid aggregation based on direct observation of oligomers.


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Authors
Shammas, Sarah L 
Garcia, Gonzalo A 
Kumar, Satish 
Kjaergaard, Magnus 
Horrocks, Mathew H 
Abstract

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.

Description
Keywords
Amyloid, Humans, Kinetics, Models, Biological, Mutation, Protein Aggregation, Pathological, tau Proteins
Journal Title
Nat Commun
Conference Name
Journal ISSN
2041-1723
2041-1723
Volume Title
6
Publisher
Springer Science and Business Media LLC
Sponsorship
Biotechnology and Biological Sciences Research Council (BB/J002119/1)
Wellcome Trust (089703/Z/09/Z)
D.K. acknowledges funding from the Wellcome Trust (WT089703) and MRC. E.M. acknowledges funding from the Wellcome Trust (WT089703), DZNE and Max-Planck-Society. M.K. acknowledges fellowships from the Danish research council and the Lundbeck Foundation. N.S. and M.H.H acknowledge funding from the Augustus Newman foundation. G.A.G is funded by the Schiff Foundation. T.P.J.K acknowledges funding from the ERC, Augustus Newman Foundation and the BBSRC.