Hyperphosphorylated tau self-assembles into amorphous aggregates eliciting TLR4-dependent responses.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
16 05 2022
16 05 2022
Historique:
received:
08
04
2021
accepted:
28
04
2022
entrez:
16
5
2022
pubmed:
17
5
2022
medline:
20
5
2022
Statut:
epublish
Résumé
Soluble aggregates of the microtubule-associated protein tau have been challenging to assemble and characterize, despite their important role in the development of tauopathies. We found that sequential hyperphosphorylation by protein kinase A in conjugation with either glycogen synthase kinase 3β or stress activated protein kinase 4 enabled recombinant wild-type tau of isoform 0N4R to spontaneously polymerize into small amorphous aggregates in vitro. We employed tandem mass spectrometry to determine the phosphorylation sites, high-resolution native mass spectrometry to measure the degree of phosphorylation, and super-resolution microscopy and electron microscopy to characterize the morphology of aggregates formed. Functionally, compared with the unmodified aggregates, which require heparin induction to assemble, these self-assembled hyperphosphorylated tau aggregates more efficiently disrupt membrane bilayers and induce Toll-like receptor 4-dependent responses in human macrophages. Together, our results demonstrate that hyperphosphorylated tau aggregates are potentially damaging to cells, suggesting a mechanism for how hyperphosphorylation could drive neuroinflammation in tauopathies.
Identifiants
pubmed: 35577786
doi: 10.1038/s41467-022-30461-x
pii: 10.1038/s41467-022-30461-x
pmc: PMC9110413
doi:
Substances chimiques
Protein Isoforms
0
TLR4 protein, human
0
Toll-Like Receptor 4
0
tau Proteins
0
Heparin
9005-49-6
Glycogen Synthase Kinase 3 beta
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2692Subventions
Organisme : Wellcome Trust
ID : 107032AIA
Pays : United Kingdom
Organisme : Medical Research Council
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 108045/Z/15/Z
Pays : United Kingdom
Informations de copyright
© 2022. The Author(s).
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