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.

Structure of Tau filaments in Prion protein amyloidoses

“…We observe K 317 to be ubiquitinated in AD, PrP-CAA (Q160X) and GSS (F198S), suggesting that the extra densities observed by cryo-EM near this residue in PrP-CAA (Q160X) and GSS (F198S) correspond to ubiquitination at this lysine. We also observe PTMs that have been reported to be important in Tau fibrillization and propagation in AD [27,28], for example, phosphorylation at T 231 , thought to be central to the initial steps of Tau detachment from microtubules and subsequent aggregation [1,2], is found in our cases of AD, PrP-CAA (Q160X) and GSS (F198S). We also observe PTMs within the two hexapeptide motifs, 275 VQIINK 280 and 306 VQIVYK 310 , which are known to be the minimum required motifs for Tau protein aggregation [39].…”

All Roads Lead to Rome: Different Molecular Players Converge to Common Toxic Pathways in Neurodegeneration

“…As a protein rich in lysine residues, tau has a high susceptibility toward ubiquitination. There are only three E3 ligases competent to ubiquitinated tau: The C-terminus of the Hsc70-interacting protein (CHIP), the TNF receptor-associated factor 6 (TRAF6), and axotrophin/MARCH7 [ 99 , 100 , 101 , 102 ]. Each of these E3 ligases ubiquitinates tau through different residues, suggesting that each ligase modulates tau degradation by different mechanisms.…”

“…CHIP ubiquitinates tau through K48 or K63 residues and thus, regulates tau degradation via both proteasomal and autophagy systems. On the other hand, the E3 ligase TRAF6 ubiquitinates tau via K63, suggesting that ubiquitination mediated by this enzyme may regulate the degradation of tau in the ALP only [ 102 ]. However, phosphorylation of tau at alternative sites prevents ubiquitination and subsequent clearance [ 102 ].…”

Astrocytes in Neurodegenerative Diseases: A Perspective from Tauopathy and α-Synucleinopathy

“…Post-translational modifications (PTMs) of Tau such as phosphorylation, acetylation, ubiquitination, SUMOylation, methylation, and glycation have long been recognized as a critical contributing factor to tauopathies [ 17 , 18 , 19 , 20 , 21 ]. Tau PTMs may enable the formation of the highly ordered β-sheet structures, which facilitates the formation of filamentous Tau inclusions, as indicated by a recent study that reported a role of Tau ubiquitination in filament formation and strain specification [ 22 ].…”