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

Sarah L Shammas; Gonzalo A Garcia; Satish Kumar; Magnus Kjaergaard; Mathew H Horrocks; Nadia Shivji; Eva Mandelkow; Tuomas P J Knowles; Eckhard Mandelkow; David Klenerman

doi:10.1038/ncomms8025

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

Sarah L Shammas, Gonzalo A Garcia, Satish Kumar, Magnus Kjaergaard, Mathew H Horrocks, Nadia Shivji, Eva Mandelkow, Tuomas P J Knowles, Eckhard Mandelkow, David Klenerman

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

162 Citations (Scopus)

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.

Original language	English
Journal	Nature Communications
Volume	6
Pages (from-to)	7025
ISSN	2041-1723
DOIs	https://doi.org/10.1038/ncomms8025
Publication status	Published - 2015
Externally published	Yes

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title = "A mechanistic model of tau amyloid aggregation based on direct observation of oligomers",

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.",

author = "Shammas, {Sarah L} and Garcia, {Gonzalo A} and Satish Kumar and Magnus Kjaergaard and Horrocks, {Mathew H} and Nadia Shivji and Eva Mandelkow and Knowles, {Tuomas P J} and Eckhard Mandelkow and David Klenerman",

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T1 - A mechanistic model of tau amyloid aggregation based on direct observation of oligomers

AU - Shammas, Sarah L

AU - Garcia, Gonzalo A

AU - Kumar, Satish

AU - Kjaergaard, Magnus

AU - Horrocks, Mathew H

AU - Shivji, Nadia

AU - Mandelkow, Eva

AU - Knowles, Tuomas P J

AU - Mandelkow, Eckhard

AU - Klenerman, David

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

U2 - 10.1038/ncomms8025

DO - 10.1038/ncomms8025

M3 - Journal article

C2 - 25926130

SN - 2041-1723

VL - 6

SP - 7025

JO - Nature Communications

JF - Nature Communications

ER -

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

Abstract

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