TY  - JOUR
AU  - Chakraborty, Pijush
AU  - Rivière, Gwladys
AU  - Hebestreit, Alina
AU  - de Opakua, Alain Ibáñez
AU  - Vorberg, Ina M
AU  - Andreas, Loren B
AU  - Zweckstetter, Markus
TI  - Acetylation discriminates disease-specific tau deposition.
JO  - Nature Communications
VL  - 14
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DZNE-2023-00955
SP  - 5919
PY  - 2023
AB  - 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.
KW  - Humans
KW  - 14-3-3 Proteins
KW  - Acetylation
KW  - Alzheimer Disease
KW  - tau Proteins
KW  - Tauopathies
KW  - 14-3-3 Proteins (NLM Chemicals)
KW  - tau Proteins (NLM Chemicals)
KW  - MAPT protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:37739953
C2  - pmc:PMC10517010
DO  - DOI:10.1038/s41467-023-41672-1
UR  - https://pub.dzne.de/record/264175
ER  -