An HDAC6-dependent surveillance mechanism suppresses tau-mediated neurodegeneration and cognitive decline

Hanna Trzeciakiewicz, Deepa Ajit, Jui-Heng Tseng, Youjun Chen, Aditi Ajit, Zarin Tabassum, Rebecca Lobrovich, Claire Peterson, Natallia V. Riddick, Michelle S. Itano, Ashutosh Tripathy, Sheryl S. Moy, Virginia M. Y. Lee, John Q. Trojanowski, David J. Irwin and Todd J. Cohen ()
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Hanna Trzeciakiewicz: University of North Carolina
Deepa Ajit: University of North Carolina
Jui-Heng Tseng: University of North Carolina
Youjun Chen: University of North Carolina
Aditi Ajit: University of North Carolina
Zarin Tabassum: University of North Carolina
Rebecca Lobrovich: University of Pennsylvania
Claire Peterson: University of Pennsylvania
Natallia V. Riddick: University of North Carolina
Michelle S. Itano: University of North Carolina
Ashutosh Tripathy: University of North Carolina
Sheryl S. Moy: University of North Carolina
Virginia M. Y. Lee: University of Pennsylvania
John Q. Trojanowski: University of Pennsylvania
David J. Irwin: University of Pennsylvania
Todd J. Cohen: University of North Carolina

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: Abstract Tauopathies including Alzheimer’s disease (AD) are marked by the accumulation of aberrantly modified tau proteins. Acetylated tau, in particular, has recently been implicated in neurodegeneration and cognitive decline. HDAC6 reversibly regulates tau acetylation, but its role in tauopathy progression remains unclear. Here, we identified an HDAC6-chaperone complex that targets aberrantly modified tau. HDAC6 not only deacetylates tau but also suppresses tau hyperphosphorylation within the microtubule-binding region. In neurons and human AD brain, HDAC6 becomes co-aggregated within focal tau swellings and human AD neuritic plaques. Using mass spectrometry, we identify a novel HDAC6-regulated tau acetylation site as a disease specific marker for 3R/4R and 3R tauopathies, supporting uniquely modified tau species in different neurodegenerative disorders. Tau transgenic mice lacking HDAC6 show reduced survival characterized by accelerated tau pathology and cognitive decline. We propose that a HDAC6-dependent surveillance mechanism suppresses toxic tau accumulation, which may protect against the progression of AD and related tauopathies.

Date: 2020
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DOI: 10.1038/s41467-020-19317-4

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