Acetylation discriminates disease-specific tau deposition

Pijush Chakraborty, Gwladys Rivière, Alina Hebestreit, Alain Ibáñez Opakua, Ina M. Vorberg, Loren B. Andreas and Markus Zweckstetter ()
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Pijush Chakraborty: German Center for Neurodegenerative Diseases (DZNE)
Gwladys Rivière: German Center for Neurodegenerative Diseases (DZNE)
Alina Hebestreit: German Center for Neurodegenerative Diseases (DZNE)
Alain Ibáñez Opakua: German Center for Neurodegenerative Diseases (DZNE)
Ina M. Vorberg: German Center for Neurodegenerative Diseases (DZNE)
Loren B. Andreas: Max Planck Institute for Multidisciplinary Sciences
Markus Zweckstetter: German Center for Neurodegenerative Diseases (DZNE)

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41672-1

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