The acetylation of tau inhibits its function and promotes pathological tau aggregation

Todd J. Cohen, Jing L. Guo, David E. Hurtado, Linda K. Kwong, Ian P. Mills, John Q. Trojanowski and Virginia M. Y. Lee ()
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Todd J. Cohen: Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, 3rd floor Maloney Building, 3600 Spruce Street
Jing L. Guo: Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, 3rd floor Maloney Building, 3600 Spruce Street
David E. Hurtado: Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, 3rd floor Maloney Building, 3600 Spruce Street
Linda K. Kwong: Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, 3rd floor Maloney Building, 3600 Spruce Street
Ian P. Mills: Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, 3rd floor Maloney Building, 3600 Spruce Street
John Q. Trojanowski: Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, 3rd floor Maloney Building, 3600 Spruce Street
Virginia M. Y. Lee: Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, 3rd floor Maloney Building, 3600 Spruce Street

Nature Communications, 2011, vol. 2, issue 1, 1-9

Abstract: Abstract The microtubule associated protein tau promotes neuronal survival through binding and stabilization of MTs. Phosphorylation regulates tau–microtubule interactions and hyperphosphorylation contributes to the aberrant formation of insoluble tau aggregates in Alzheimer's disease (AD) and related tauopathies1. However, other pathogenic post-translational tau modifications have not been well characterized. Here we demonstrate that tau acetylation inhibits tau function via impaired tau–microtubule interactions and promotes pathological tau aggregation. Mass spectrometry analysis identified specific lysine residues, including lysine 280 (K280) within the microtubule-binding motif as the major sites of tau acetylation. Immunohistochemical and biochemical studies of brains from tau transgenic mice and patients with AD and related tauopathies showed that acetylated tau pathology is specifically associated with insoluble, Thioflavin-positive tau aggregates. Thus, tau K280 acetylation in our studies was only detected in diseased tissue, suggesting it may have a role in pathological tau transformation. This study suggests that tau K280 acetylation is a potential target for drug discovery and biomarker development for AD and related tauopathies.

Date: 2011
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DOI: 10.1038/ncomms1255

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