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Acetylation discriminates disease-specific tau deposition.


ABSTRACT: Pathogenic aggregation of the protein tau is a hallmark of Alzheimer's disease and several other tauopathies. Tauopathies are characterized by the deposition of specific tau isoforms as disease-related tau filament structures. The molecular processes that determine isoform-specific deposition of tau are however enigmatic. Here we show that acetylation of tau discriminates its isoform-specific aggregation. We reveal that acetylation strongly attenuates aggregation of four-repeat tau protein, but promotes amyloid formation of three-repeat tau. We further identify acetylation of lysine 298 as a hot spot for isoform-specific tau aggregation. Solid-state NMR spectroscopy demonstrates that amyloid fibrils formed by unmodified and acetylated three-repeat tau differ in structure indicating that site-specific acetylation modulates tau structure. The results implicate acetylation as a critical regulator that guides the selective aggregation of three-repeat tau and the development of tau isoform-specific neurodegenerative diseases.

SUBMITTER: Chakraborty P 

PROVIDER: S-EPMC10517010 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Acetylation discriminates disease-specific tau deposition.

Chakraborty Pijush P   Rivière Gwladys G   Hebestreit Alina A   de Opakua Alain Ibáñez AI   Vorberg Ina M IM   Andreas Loren B LB   Zweckstetter Markus M  

Nature communications 20230922 1


Pathogenic aggregation of the protein tau is a hallmark of Alzheimer's disease and several other tauopathies. Tauopathies are characterized by the deposition of specific tau isoforms as disease-related tau filament structures. The molecular processes that determine isoform-specific deposition of tau are however enigmatic. Here we show that acetylation of tau discriminates its isoform-specific aggregation. We reveal that acetylation strongly attenuates aggregation of four-repeat tau protein, but  ...[more]

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