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Nat Neurosci. 2015 Aug;18(8):1183-9. doi: 10.1038/nn.4067. Epub 2015 Jul 20.

Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice.

Author information

1
1] Gladstone Institute of Neurological Disease, San Francisco, California, USA. [2] Biochemistry, Cellular and Molecular Biology Graduate Program, Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
2
Mass Spectrometry Facility, Department of Pharmaceutical Chemistry, University of California, San Francisco, California, USA.
3
1] Gladstone Institute of Neurological Disease, San Francisco, California, USA. [2] Department of Neurology, University of California, San Francisco, California, USA.

Abstract

The microtubule-associated protein tau has been implicated in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. Reducing tau levels ameliorates AD-related synaptic, network, and behavioral abnormalities in transgenic mice expressing human amyloid precursor protein (hAPP). We used mass spectrometry to characterize the post-translational modification of endogenous tau isolated from wild-type and hAPP mice. We identified seven types of tau modifications at 63 sites in wild-type mice. Wild-type and hAPP mice had similar modifications, supporting the hypothesis that neuronal dysfunction in hAPP mice is enabled by physiological forms of tau. Our findings provide clear evidence for acetylation and ubiquitination of the same lysine residues; some sites were also targeted by lysine methylation. Our findings refute the hypothesis of extensive O-linked N-acetylglucosamine (O-GlcNAc) modification of endogenous tau. The complex post-translational modification of physiological tau suggests that tau is regulated by diverse mechanisms.

PMID:
26192747
DOI:
10.1038/nn.4067
[Indexed for MEDLINE]

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