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.
Highlights
Post-translational modifications (PTMs) refer to the modifications that occur in a protein either shortly after its translation by ribosomes or after its folding and localization are complete [1]
Other PTMs affect the process of protein degradation indirectly. This is the case for phosphorylation and acetylation, both of which can modify amino acid sequences known as degrons, which are important for protein degradation
Tau protein can be efficiently degraded by chaperone-mediated autophagy (CMA) as long as the KFERQ motifs are not blocked by PTMs [252]
Summary
Post-translational modifications (PTMs) refer to the modifications that occur in a protein either shortly after its translation by ribosomes or after its folding and localization are complete [1]. PTMs alter the charge and hydrophobicity (electrostatics) of a protein, which in turn induces structural changes that influence protein function, protein-protein interactions, and protein aggregation [3, 4]. In this way, PTMs can affect the clearance of proteins by regulating the functionality of degrons, peptide sequences that target a protein for degradation [5]. The same PTMs that regulate tau function have the ability to induce alterations in its clearance, conformation, and aggregation potential [23]. We summarize strengths and limitations of current approaches to the study of PTMs (section Approaches and Limitations) and provide concluding remarks (section Concluding Remarks)
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