Hsp70 Inhibits the Nucleation and Elongation of Tau and Sequesters Tau Aggregates with High Affinity

Franziska Kundel; Suman De; Patrick Flagmeier; Mathew H Horrocks; Magnus Kjaergaard; Sarah L Shammas; Sophie E Jackson; Christopher M Dobson; David  Klenerman

doi:10.1021/acschembio.7b01039

Hsp70 Inhibits the Nucleation and Elongation of Tau and Sequesters Tau Aggregates with High Affinity

Franziska Kundel, Suman De, Patrick Flagmeier, Mathew H Horrocks, Magnus Kjaergaard, Sarah L Shammas, Sophie E Jackson, Christopher M Dobson, David Klenerman

Aarhus Institute of Advanced Studies

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

83 Citations (Scopus)

Abstract

As a key player of the protein quality control network of the cell, the molecular chaperone Hsp70 inhibits the aggregation of the amyloid protein tau. To date, the mechanism of this inhibition and the tau species targeted by Hsp70 remain unknown. This is partly due to the inherent difficulty of studying amyloid aggregates because of their heterogeneous and transient nature. Here, we used ensemble and single-molecule fluorescence measurements to dissect how Hsp70 counteracts the self-assembly process of the K18 ΔK280 tau variant. We found that Hsp70 blocks the early stages of tau aggregation by suppressing the formation of tau nuclei. Additionally, Hsp70 sequesters oligomers and mature tau fibrils with nanomolar affinity into a protective complex, efficiently neutralizing their ability to damage membranes and seed further tau aggregation. Our results provide novel insights into the molecular mechanisms by which the chaperone Hsp70 counteracts the formation, propagation, and toxicity of tau aggregates.

Original language	English
Journal	ACS chemical biology
Volume	13
Issue	3
Pages (from-to)	636-646
Number of pages	11
ISSN	1554-8929
DOIs	https://doi.org/10.1021/acschembio.7b01039
Publication status	Published - 2018

Keywords

ALPHA-SYNUCLEIN
ALZHEIMERS-DISEASE
CHAPERONE
FIBRILS
NEURONAL PC12 CELLS
OLIGOMERS
P301S TAU
PAIRED HELICAL FILAMENT
PROTEIN HOMEOSTASIS
SINGLE-MOLECULE FLUORESCENCE

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10.1021/acschembio.7b01039Licence: CC BY

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374916/pdf/cb7b01039.pdfLicence: CC BY

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title = "Hsp70 Inhibits the Nucleation and Elongation of Tau and Sequesters Tau Aggregates with High Affinity",

abstract = "As a key player of the protein quality control network of the cell, the molecular chaperone Hsp70 inhibits the aggregation of the amyloid protein tau. To date, the mechanism of this inhibition and the tau species targeted by Hsp70 remain unknown. This is partly due to the inherent difficulty of studying amyloid aggregates because of their heterogeneous and transient nature. Here, we used ensemble and single-molecule fluorescence measurements to dissect how Hsp70 counteracts the self-assembly process of the K18 ΔK280 tau variant. We found that Hsp70 blocks the early stages of tau aggregation by suppressing the formation of tau nuclei. Additionally, Hsp70 sequesters oligomers and mature tau fibrils with nanomolar affinity into a protective complex, efficiently neutralizing their ability to damage membranes and seed further tau aggregation. Our results provide novel insights into the molecular mechanisms by which the chaperone Hsp70 counteracts the formation, propagation, and toxicity of tau aggregates.",

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author = "Franziska Kundel and Suman De and Patrick Flagmeier and Horrocks, {Mathew H} and Magnus Kjaergaard and Shammas, {Sarah L} and Jackson, {Sophie E} and Dobson, {Christopher M} and David Klenerman",

year = "2018",

doi = "10.1021/acschembio.7b01039",

language = "English",

volume = "13",

pages = "636--646",

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T1 - Hsp70 Inhibits the Nucleation and Elongation of Tau and Sequesters Tau Aggregates with High Affinity

AU - Kundel, Franziska

AU - De, Suman

AU - Flagmeier, Patrick

AU - Horrocks, Mathew H

AU - Kjaergaard, Magnus

AU - Shammas, Sarah L

AU - Jackson, Sophie E

AU - Dobson, Christopher M

AU - Klenerman, David

PY - 2018

Y1 - 2018

N2 - As a key player of the protein quality control network of the cell, the molecular chaperone Hsp70 inhibits the aggregation of the amyloid protein tau. To date, the mechanism of this inhibition and the tau species targeted by Hsp70 remain unknown. This is partly due to the inherent difficulty of studying amyloid aggregates because of their heterogeneous and transient nature. Here, we used ensemble and single-molecule fluorescence measurements to dissect how Hsp70 counteracts the self-assembly process of the K18 ΔK280 tau variant. We found that Hsp70 blocks the early stages of tau aggregation by suppressing the formation of tau nuclei. Additionally, Hsp70 sequesters oligomers and mature tau fibrils with nanomolar affinity into a protective complex, efficiently neutralizing their ability to damage membranes and seed further tau aggregation. Our results provide novel insights into the molecular mechanisms by which the chaperone Hsp70 counteracts the formation, propagation, and toxicity of tau aggregates.

AB - As a key player of the protein quality control network of the cell, the molecular chaperone Hsp70 inhibits the aggregation of the amyloid protein tau. To date, the mechanism of this inhibition and the tau species targeted by Hsp70 remain unknown. This is partly due to the inherent difficulty of studying amyloid aggregates because of their heterogeneous and transient nature. Here, we used ensemble and single-molecule fluorescence measurements to dissect how Hsp70 counteracts the self-assembly process of the K18 ΔK280 tau variant. We found that Hsp70 blocks the early stages of tau aggregation by suppressing the formation of tau nuclei. Additionally, Hsp70 sequesters oligomers and mature tau fibrils with nanomolar affinity into a protective complex, efficiently neutralizing their ability to damage membranes and seed further tau aggregation. Our results provide novel insights into the molecular mechanisms by which the chaperone Hsp70 counteracts the formation, propagation, and toxicity of tau aggregates.

KW - ALPHA-SYNUCLEIN

KW - ALZHEIMERS-DISEASE

KW - CHAPERONE

KW - FIBRILS

KW - NEURONAL PC12 CELLS

KW - OLIGOMERS

KW - P301S TAU

KW - PAIRED HELICAL FILAMENT

KW - PROTEIN HOMEOSTASIS

KW - SINGLE-MOLECULE FLUORESCENCE

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DO - 10.1021/acschembio.7b01039

M3 - Journal article

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SN - 1554-8929

VL - 13

SP - 636

EP - 646

JO - ACS chemical biology

JF - ACS chemical biology

IS - 3

ER -

Hsp70 Inhibits the Nucleation and Elongation of Tau and Sequesters Tau Aggregates with High Affinity

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