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

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

doi:10.1038/ncomms8025

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.

Highlights

Protein aggregation plays a key role in neurodegenerative disease, giving rise to small oligomers that may become cytotoxic to cells
Alzheimer’s disease is characterized by the deposition of two distinct types of aggregates—extracellular plaques composed of Ab peptides and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein
Tau is a microtubule-binding protein that can aggregate into filaments, which are amyloid in nature and are the major constituents of neurofibrillary tangles in the neurons of Alzheimer-diseased brains[3]

Summary

Introduction

Protein aggregation plays a key role in neurodegenerative disease, giving rise to small oligomers that may become cytotoxic to cells. 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. Tau is a microtubule-binding protein that can aggregate into filaments, which are amyloid in nature (based on cross-b structure) and are the major constituents of neurofibrillary tangles in the neurons of Alzheimer-diseased brains[3]. Tau is rich in polar amino acids, which renders it a highly soluble protein with little secondary structure[6] even once bound to the microtubule[7]. It is a surprise that this protein assembles into amyloid structures

Methods

Results

Conclusion