Post-Translational Modifications in Tau Protein and Neurodegenerative Disorders

Tau is a microtubule-associated protein that undergoes a variety of post-translational modifications (PTMs) which regulate its normal function, localisation and turnover. In neurodegenerative tauopathies such as Alzheimer’s disease, frontotemporal lobar degeneration and chronic traumatic encephalopathy, aberrant phosphorylation, acetylation, ubiquitination and other PTMs drive pathological misfolding, aggregation and propagation of tau. Phosphorylation at multiple serine and threonine residues often precedes filament formation, whereas lysine acetylation can either inhibit or promote isoform-specific assembly of tau fibrils. Ubiquitination mediates tau clearance via the proteasome and autophagic pathways, yet may also modify mature aggregates. Emerging evidence highlights competitive and combinatorial crosstalk among PTMs, creating a dynamic “tau code” that governs microtubule stability, synaptic integrity and neurotoxicity. Dysregulation of chaperone-mediated autophagy and macroautophagy further exacerbates tau accumulation and cell-to-cell spread. Advances in understanding these modifications have identified novel biomarkers of disease stage and therapeutic targets to restore proteostasis and neuronal resilience.

Research from Nature Portfolio

Recent studies have revealed that site-specific acetylation critically influences tau isoform aggregation. Acetylation at a hot-spot lysine discriminates three-repeat and four-repeat tau by attenuating assembly of the latter while promoting fibrillisation of the former. Structural analyses show that acetylation induces distinct conformations in three-repeat tau amyloids, implicating this modification in selective vulnerability across tauopathies.

Work on tau degradation has demonstrated that acetylated tau preferentially evades chaperone-mediated autophagy, leading to rerouting towards macroautophagy and endosomal microautophagy. This rerouting impairs lysosomal function, promotes extracellular release of pathogenic tau and enhances cell-to-cell propagation in mouse models. Similar mechanisms of chaperone-mediated autophagy failure have been identified in lysosomes from human tauopathy brains, linking PTM-driven autophagy dysregulation to disease progression.

Post-Translational Modifications in Tau Protein and Neurodegenerative Disorders publication trend

The graph below shows the total number of articles in post-translational modifications in tau protein and neurodegenerative disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Post-Translational Modification: A chemical alteration of a protein after its synthesis, affecting function or stability.

Acetylation: Addition of an acetyl group to lysine residues, modulating charge and protein interactions.

Ubiquitination: Covalent attachment of ubiquitin to lysine residues, marking proteins for degradation or altering their trafficking.

Chaperone-Mediated Autophagy: Selective lysosomal degradation pathway in which chaperone proteins deliver substrates directly to the lysosome.

Macroautophagy: Bulk sequestration of cytoplasmic material into autophagosomes for lysosomal degradation.

Proteostasis: The cellular network that regulates protein synthesis, folding, modification and clearance to maintain protein homeostasis.

References

1. Anti-acetylated-tau immunotherapy is neuroprotective in tauopathy and brain injury. Molecular Neurodegeneration (2024).
2. Acetylation discriminates disease-specific tau deposition. Nature Communications (2023).
3. Site‐Specific Ubiquitination of Tau Amyloids Promoted by the E3 Ligase CHIP. Angewandte Chemie International Edition (2023).
4. Evolutionarily conserved regulators of tau identify targets for new therapies. Neuron (2023).
5. Tau Post-translational Modifications: Dynamic Transformers of Tau Function, Degradation, and Aggregation. Frontiers in Neurology (2021).
6. An acetylation–phosphorylation switch that regulates tau aggregation propensity and function. Journal of Biological Chemistry (2017).
7. Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice. Nature Communications (2021).
8. Tau in neurodegenerative diseases: molecular mechanisms, biomarkers, and therapeutic strategies. Translational Neurodegeneration (2024).