A mechanistic model of tau amyloid aggregation based on direct observation of oligomers.
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.
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Sarah L
000000034489140X
SL
Shammas
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Gonzalo A
GA
Garcia
DZNE, German Center for Neurodegenerative Diseases, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
Satish
S
Kumar
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Magnus
0000000270209366
M
Kjaergaard
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Mathew H
MH
Horrocks
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Nadia
N
Shivji
1] DZNE, German Center for Neurodegenerative Diseases, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany [2] CAESAR Research Center, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany.
Eva
E
Mandelkow
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Tuomas P J
TP
Knowles
1] DZNE, German Center for Neurodegenerative Diseases, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany [2] CAESAR Research Center, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany [3] Max-Planck-Institute for Metabolism Research, Hamburg Outstation, c/o DESY, Notkestrasse 85, 22607 Hamburg, Germany.
Eckhard
E
Mandelkow
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
David
D
Klenerman
D000682:Amyloid / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D009154:Mutation; D066263:Protein Aggregation, Pathological; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D000682:Amyloid; D016875:tau Proteins