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  • Review Article
  • Published:

Cellular and pathological functions of tau

Abstract

Tau protein is involved in various cellular processes, including having a canonical role in binding and stabilization of microtubules in neurons. Tauopathies are neurodegenerative diseases marked by the abnormal accumulation of tau protein aggregates in neurons, as seen, for example, in conditions such as frontotemporal dementia and Alzheimer disease. Mutations in tau coding regions or that disrupt tau mRNA splicing, tau post-translational modifications and cellular stress factors (such as oxidative stress and inflammation) increase the tendency of tau to aggregate and interfere with its clearance. Pathological tau is strongly implicated in the progression of neurodegenerative diseases, and the propagation of tau aggregates is associated with disease severity. Recent technological advancements, including cryo-electron microscopy and disease models derived from human induced pluripotent stem cells, have increased our understanding of tau-related pathology in neurodegenerative conditions. Substantial progress has been made in deciphering tau aggregate structures and the molecular mechanisms that underlie protein aggregation and toxicity. In this Review, we discuss recent insights into the diverse cellular functions of tau and the pathology of tau inclusions and explore the potential for therapeutic interventions.

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Fig. 1: Tau isoforms, disease-causing mutations and post-translational modifications.
Fig. 2: Diverse physiological functions of soluble tau.
Fig. 3: Tau protein impaired homeostasis and pathological spread.
Fig. 4: Neuronal mechanisms of tau pathology.
Fig. 5: Non-cell-autonomous mechanisms of tau pathology.

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Acknowledgements

The authors thank Gan lab members for insightful discussions.

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Authors and Affiliations

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All authors researched data for the Review and discussed its content, and all authors contributed to the writing, reviewing and editing of the manuscript before submission.

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Correspondence to Li Gan.

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Related links

MAPT mutations on Alzforum: https://www.alzforum.org/mutations/mapt

Glossary

α-Synuclein

A neuronal protein that aggregates to form Lewy bodies, a characteristic of Parkinson disease and other synucleinopathies.

Adaptive immune response

A type of immunity that specifically recognizes pathogens and generates memory cells for long-term defence.

Amyloid-β

A peptide of 36–43 amino acids formed after the cleavage of amyloid precursor protein; this peptide aggregates to form plaques in Alzheimer disease.

APEX mapping

A method for labelling and identifying protein–protein interactions in cells using an engineered ascorbic acid peroxidase (APEX) enzyme.

Behavioural deficits

Impairments in normal behaviour observed in neurodegenerative disorders, including cognitive, emotional and social behaviour.

Blood–brain barrier

A selective, semi-permeable endothelial cell barrier that surrounds blood vessels in the brain and both allows passage of nutrients from the blood and protects the brain from neurotoxic substances.

Braak stages

Neuropathological classifications in a system used to assign the degree of neurofibrillary tangle pathology in a diseased brain.

Caspase 9

An enzyme that has an essential role in initiation of apoptosis (programmed cell death).

Chaperone-mediated autophagy

A chaperone-dependent protein degradation pathway in which proteins are directly translocated into lysosomes.

Cyclic GMP-AMP synthase

(cGAS). An enzyme that acts as an innate immune sensor that detects cytosolic DNA fragments and triggers an inflammatory response as part of the cGAS–STING pathway.

Deubiquitinases

Enzymes that remove ubiquitin molecules from proteins.

Dynamic instability

Periods of rapid, alternating growth and shrinkage of microtubules.

End-binding proteins

Proteins that associate with the plus ends of microtubules and regulate their dynamics.

Endoplasmic reticulum-associated degradation

A cellular pathway that targets misfolded proteins in the endoplasmic reticulum for proteasomal degradation.

Excitotoxicity

Neuronal damage and death triggered by excessive stimulation by excitatory neurotransmitters such as glutamate.

Filopodia

Thin, dynamic, actin-enriched membrane projections on cells involved in cell migration, which serve as precursors for dendritic spines.

Firing rate

The frequency at which a neuron produces action potentials per unit time.

Granulovacuolar degeneration

The accumulation of large, double membrane-bound bodies that contain granules within degenerating neurons, commonly seen in Alzheimer disease.

Intrinsically disordered

Describes a protein or regions in a protein that lack a stable 3D structure.

Long-term potentiation

A persistent strengthening of synaptic connections that results in a long-lasting increase in synaptic transmission.

Major histocompatibility complex class II

(MHC II). A set of molecules expressed on the surface of immune cells that present processed antigens to T cells.

Mitophagy

The selective degradation of dysfunctional mitochondria by autophagy.

Mushroom spines

Small, bulbous, dendritic protrusions associated with long-term potentiation and sustained synaptic transmission.

Neuronal cell cycle re-entry

An process by which neurons aberrantly re-enter the cell cycle, which leads to non-programmed cell death.

NLRP3 inflammasome

A multiprotein complex that activates innate inflammatory responses and is aberrantly activated in inflammatory diseases.

Penetrant mutations

Genetic mutations that consistently present a particular morphological or physiological phenotype.

Primary tauopathies

A class of neurodegenerative diseases in which tau pathology is the main pathological hallmark.

Proteinopathic disease

A disease caused by the misfolding and aggregation of proteins.

Respirasome

A supercomplex of mitochondrial membrane proteins involved in cellular respiration.

Retromer complex

A protein complex involved in the trafficking of proteins from endosomes to the trans-Golgi network and cell surface.

Secondary tauopathies

A class of neurodegenerative diseases in which tau pathology occurs as a secondary feature.

SNARE protein

Member of a large family of proteins that mediate the docking and fusion of vesicles with target membranes.

Stem–loop structure

In DNA, a structure consisting of an intramolecular loop that occurs when the sequences of two adjacent regions on the same strand are complementary to one another. Also known as a hairpin structure.

Synaptosomes

A subcellular fraction isolated from brain tissue that contains complete synaptic terminals.

Ubiquitin linkages

Covalent bonds between ubiquitin molecules, or between a ubiquitin molecule and a target substrate, which tag a protein for degradation or other processing.

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Parra Bravo, C., Naguib, S.A. & Gan, L. Cellular and pathological functions of tau. Nat Rev Mol Cell Biol 25, 845–864 (2024). https://doi.org/10.1038/s41580-024-00753-9

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