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

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

Meaghan Morris et al. Nat Neurosci. 2015 Aug.

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.

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Figures

Figure 1
Figure 1

PTMs identified in endogenous mouse tau. Mouse tau was isolated from brains of wildtype mice, and PTMs were assigned by mass spectrometry. Modifications are shown on the longest tau isoform expressed in the mouse central nervous system (430 amino acids). All assigned endogenous tau modifications are shown in the top panel (a). The lower panels show subsets of the same modifications, indicating those that are novel (b) or separating them by the amino acid modified: arginine (c), lysine (d), and serine/threonine/tyrosine (e). The N-terminal exons expressed in mouse tau 430 are shown in green, the proline-rich region in teal, and the four microtubule-binding repeats in orange. Only PTMs with unambiguously assigned sites from wildtype mice (Table 2) are indicated, and all sites are positioned to scale. Note that some amino acid residues can be alternately modified and that these modifications are mutually exclusive (e.g., ubiquitination, mono-/di-methylation, and acetylation). The N-terminal exons N1 and N2 are subject to alternative splicing.

Figure 2
Figure 2

Differential modification of tau in the PSD. (a) Western blot showing PSD95, tau, and α-synuclein levels in two different mice from a replicate cohort at each step of PSD fractionation. Full-length blots are presented in Supplementary Fig. 4. (b) Quantification of western blot signals. n = 8 mice, 5–6 months of age. Values were normalized to the average level of the respective protein in the cytosolic/membrane fraction (arbitrarily defined as 1.0). (c) Quantification of the five most common tau modifications in the PSD fraction relative to average levels in hippocampal and cortical whole lysate (arbitrarily defined as 1.0). Cohort B: n = 10 or 12 mice per group, 7–10 months of age (Supplementary Table 4). Because of site ambiguity, peptide sequences containing modified sites are indicated; di- and tri- denote doubly and triply modified peptides, respectively. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001 vs. whole lysate or as indicated by brackets (paired (b) or unpaired (c) t test with Holm correction). Welch's correction was applied in (c) to the analysis of peptides di-p386–404 and tri-p386–404 due to unequal variance. Cyt/Mem, cytosolic- and membrane-containing fraction; Cyt, cytosolic fraction; Mem, membrane fraction; Non-PSD, fraction remaining after PSD extraction; ns, not significant; RU, relative units; Syn, synaptosomal fraction. Quantitative values are means ± SEM. Some error bars in (b) are too small to see.

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