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

Author

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  • Sarah L. Shammas

    (University of Cambridge)

  • Gonzalo A. Garcia

    (University of Cambridge)

  • Satish Kumar

    (DZNE, German Center for Neurodegenerative Diseases
    Present address: Institute of Forensic Science, Gujarat Forensic Sciences University, Gandhinagar-382007, Gujarat, India)

  • Magnus Kjaergaard

    (University of Cambridge
    Present address: iNANO, Aarhus University, DK-8000 Aarhus C, Denmark)

  • Mathew H. Horrocks

    (University of Cambridge)

  • Nadia Shivji

    (University of Cambridge)

  • Eva Mandelkow

    (DZNE, German Center for Neurodegenerative Diseases
    CAESAR Research Center)

  • Tuomas P.J. Knowles

    (University of Cambridge)

  • Eckhard Mandelkow

    (DZNE, German Center for Neurodegenerative Diseases
    CAESAR Research Center
    Max-Planck-Institute for Metabolism Research, Hamburg Outstation, c/o DESY)

  • David Klenerman

    (University of Cambridge)

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.

Suggested Citation

  • 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, 2015. "A mechanistic model of tau amyloid aggregation based on direct observation of oligomers," Nature Communications, Nature, vol. 6(1), pages 1-10, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8025
    DOI: 10.1038/ncomms8025
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    Cited by:

    1. Guilherme G. Moreira & François-Xavier Cantrelle & Andrea Quezada & Filipa S. Carvalho & Joana S. Cristóvão & Urmi Sengupta & Nicha Puangmalai & Ana P. Carapeto & Mário S. Rodrigues & Isabel Cardoso &, 2021. "Dynamic interactions and Ca2+-binding modulate the holdase-type chaperone activity of S100B preventing tau aggregation and seeding," Nature Communications, Nature, vol. 12(1), pages 1-16, December.

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