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Tau in physiology and pathology

Key Points

  • Tauopathies are classified into several groups based on the isoform composition of tau aggregates. The splicing of the gene encoding tau is regulated by multiple factors besides tau mutations.

  • Tau is a natively unfolded protein that shows no tendency for aggregation by itself. Post-translational modifications may modify the processes of tau oligomerization, aggregation and tau-induced neurodegeneration.

  • The polarized distribution of tau into the axonal compartment of neurons is determined by multiple mechanisms. In addition, part of tau is actively released into extracellular space.

  • Besides stabilizing microtubules, regulating their dynamic instability and supporting axonal transport, tau can interact with various cell components and thus serves other functions in various other processes, including neuronal activity, neurogenesis, iron export and long-term depression.

  • Pathological tau may induce neurotoxicity owing to its loss of function, toxic gain of function or its mislocalization, which mediates amyloid-β-induced toxicity.

  • Several tau- or microtubule-based therapeutic approaches have been proposed, including tau aggregation inhibitors, inhibitors of kinases targeting tau, inhibition of tau acetylation, stabilization of microtubules, reduction of tau by antisense oligonucleotides, and immunotherapy using antibodies against tau or phosphorylated tau.

Abstract

Tau is a microtubule-associated protein that has a role in stabilizing neuronal microtubules and thus in promoting axonal outgrowth. Structurally, tau is a natively unfolded protein, is highly soluble and shows little tendency for aggregation. However, tau aggregation is characteristic of several neurodegenerative diseases known as tauopathies. The mechanisms underlying tau pathology and tau-mediated neurodegeneration are debated, but considerable progress has been made in the field of tau research in recent years, including the identification of new physiological roles for tau in the brain. Here, we review the expression, post-translational modifications and functions of tau in physiology and in pathophysiology.

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Figure 1: The human MAPT gene and the splice isoforms of tau in the human brain.
Figure 2: Tau structure, domains, mutations and pathological phosphorylation sites.
Figure 3: Functions of tau.

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Acknowledgements

The authors thank E.-M. Mandelkow for critical reading of and insightful suggestions for the manuscript, and thank L. Krueger for fruitful discussions. The project was supported in part by the German Center for Neurodegenerative Diseases (DZNE), the Max Planck Society (MPG), the Tau Consortium and the Wellcome Trust/MRC Alzheimer Consortium.

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Correspondence to Yipeng Wang or Eckhard Mandelkow.

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Glossary

Paired helical filaments

(PHFs). Fibrous polymers of tau that resemble twisted filaments (originally considered to be pairs of filaments, hence the name) of 20 nm width and 80 nm crossover periodicity. Variants of PHFs are the 'straight filaments', which do not have a twisted structure.

Neurofibrillary tangles

(NFTs). Bundles of paired helical filaments in the cytosol of neurons.

Tau aggregation

An interaction between tau molecules that leads to the generation of fibrous polymers with a periodic structure.

Projection domain

The amino-terminal half of tau that projects away from microtubules when tau binds to microtubules.

Assembly domain

The carboxy-terminal portion of tau that is responsible for binding to microtubules.

Lys48 linkages

The binding of a ubiquitin molecule to another ubiquitin via the Lys48 of the seven Lys residues of ubiquitin.

Nucleation–elongation mechanism

A model that postulates that the rate-limiting step for protein aggregation is the formation of an initial oligomeric nucleus for aggregation. Once formed, polymerization can proceed via elongation, whereby protein subunits are directly added to the growing ends of the fibre.

Template-assisted model

A model developed to explain aggregation of prion protein. It proposes that the infectious scrapie prion protein serves as a template that catalyses conformational changes of normal PrPC to PrPSc, leading to PrPSc aggregation.

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Wang, Y., Mandelkow, E. Tau in physiology and pathology. Nat Rev Neurosci 17, 22–35 (2016). https://doi.org/10.1038/nrn.2015.1

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