Chakraborty, PijushPijushChakrabortyRivière, GwladysGwladysRivièreHebestreit, AlinaAlinaHebestreitde Opakua, Alain IbáñezAlain Ibáñezde OpakuaVorberg, Ina M.Ina M.VorbergAndreas, Loren B.Loren B.AndreasZweckstetter, MarkusMarkusZweckstetter2023-10-062023-10-062023https://resolver.sub.uni-goettingen.de/purl?gro-2/132964Abstract 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.enhttps://creativecommons.org/licenses/by/4.0journal_article10.1038/s41467-023-41672-141672