Tau Post-translational Modifications: Dynamic Transformers of Tau Function, Degradation, and Aggregation

Abstract

Post-translational modifications (PTMs) on tau have long been recognized as affecting protein function and contributing to neurodegeneration. The explosion of information on potential and observed PTMs on tau provides an opportunity to better understand these modifications in the context of tau homeostasis, which becomes perturbed with aging and disease. Prevailing views regard tau as a protein that undergoes abnormal phosphorylation prior to its accumulation into the toxic aggregates implicated in Alzheimer's disease (AD) and other tauopathies. However, the phosphorylation of tau may, in fact, represent part of the normal but interrupted function and catabolism of the protein. In addition to phosphorylation, tau undergoes another forms of post-translational modification including (but not limited to), acetylation, ubiquitination, glycation, glycosylation, SUMOylation, methylation, oxidation, and nitration. A holistic appreciation of how these PTMs regulate tau during health and are potentially hijacked in disease remains elusive. Recent studies have reinforced the idea that PTMs play a critical role in tau localization, protein-protein interactions, maintenance of levels, and modifying aggregate structure. These studies also provide tantalizing clues into the possibility that neurons actively choose how tau is post-translationally modified, in potentially competitive and combinatorial ways, to achieve broad, cellular programs commensurate with the distinctive environmental conditions found during development, aging, stress, and disease. Here, we review tau PTMs and describe what is currently known about their functional impacts. In addition, we classify these PTMs from the perspectives of protein localization, electrostatics, and stability, which all contribute to normal tau function and homeostasis. Finally, we assess the potential impact of tau PTMs on tau solubility and aggregation. Tau occupies an undoubtedly important position in the biology of neurodegenerative diseases. This review aims to provide an integrated perspective of how post-translational modifications actively, purposefully, and dynamically remodel tau function, clearance, and aggregation. In doing so, we hope to enable a more comprehensive understanding of tau PTMs that will positively impact future studies.

Keywords: acetylation; glycation; glycosylation; methylation; phosphorylation; proteolysis; sumoylation; ubiquitination.

Figure 1

Post-translational modifications are found throughout tau and associate with all tauopathies. (A) Schematic representation of the structural features of 2N4R tau protein. Tau exists in 6 isoforms generated by the alternative splicing of exons 2, 3, and 10 of the MAPT gene. The isoforms include 0, 1, or 2 amino-terminal inserts (blue rectangles) and three (3R) or four (4R) microtubule-binding potential repeat domains (green rectangles). (B) Pathological and genetic classification of tauopathies as they relate to post-translational modifications (PTMs). Primary tauopathies fall under the umbrella pathological term frontotemporal lobar degeneration with tau inclusions (FTLD-Tau) and include Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia with parkinsonism (FTDP-17). Alzheimer's disease, a secondary or mixed tauopathy, is characterized by the presence of extracellular inclusions containing Amyloid β (Aβ) protein. Tauopathies are also classified depending on tau isoform composing the intracellular inclusions. PiD is a 3R-predominat tauopathy, PSP, and CBD are 4R tauopathies and FTDP-17 and AD are 3R:4R tauopathies. The PTMs observed in tau, the targeted residues and the disease where they have been observed is also shown.

Figure 2

Relative frequency of post-translational modifications on tau. The 2N4R isoform of tau contains 441 amino acid residues, around 35 percent of which can potentially undergo PTMs. These residues include serine (forty-five), threonine (thirty-five), tyrosine (five), asparagine (three), arginine (fourteen), and lysine (forty-four). The most common PTMs in tau are shown on the y-axis of the bar plot. The x-axis of the plot shows the percentage of amino acid residues with solid bars showing the sites that have been identified within total potential sites shown in shaded bars. The functional groups associated with each PTM are also shown next to each bar. Since all potential phosphorylation sites have been identified, the shaded bar is completely masked by the solid bar. Similarly, in case of N-glycosylation, the specific N-glycosylation sites have not been reported and therefore, only potential sites represented by shaded bar have been shown.

Figure 3

Tau undergoes diverse post-translational modifications that often compete for the same amino acid residues. Diagram showing the polypeptide chain of the longest tau isoform 2N4R tau along with individual amino acid residues highlighting different regions/domains. The N-terminal inserts are represented with blue residue borders, proline-rich domain is represented with purple residue borders, microtubule-binding domains are represented with green residue borders (R1, R3, R4 in dark green, and R2 in light green), and disease-associated amino acid variants are highlighted in red text. The vertical black line between residues is shown for distinction between two N-terminal inserts and four microtubule-binding repeats. The colored dots represent the PTMs identified in tau (WT and mutant) in vitro and in vivo. The color code for PTMs is as follows: phosphorylation (light blue), acetylation (pink), methylation (green), glycation (yellow), ubiquitination (red), O-GlcNAcylation (orange), SUMOylation (dark blue), and nitration (purple). N-glycosylation is omitted as no specific sites have been identified. The KXGS microtubule-binding motifs are shown in pink boxes. The canonical and potential KFERQ motifs are represented with dark blue and light blue boxes, respectively. The phosphodegron motifs are highlighted with green boxes.

Figure 4

Post-translational modifications on tau impact tau function, degradation, and aggregation. PTMs can both promote and inhibit tau function, clearance, and aggregation. A non-exhaustive list of examples are illustrated here. In many cases, it is likely that cross-talk and competition between PTMs results in the specific and dynamic regulation of tau.