ArticleHuman molecular genetics2014
Acetylation of the KXGS motifs in tau is a critical determinant in modulation of tau aggregation and clearance.
Article in Human molecular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 178 papers.
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Who cites it
178 citing papers in PubMed, 286 citations in OpenAlex.
- Modifications of Lysine Residues 294 and 311 Within the Microtubule-Binding Region Alter Tau Aggregation and Tubulin Binding Equilibria.Angewandte Chemie (International ed. in English) · 2026Article
- SIRT1 in Neurodegenerative Diseases: Molecular Mechanisms, Disease Relevance, and Therapeutic Potential.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Review
- Structural Hierarchy and Maturation of Amyloid Fibrils Revealed by Interface Descriptor Analysis.Journal of chemical information and modeling · 2026Article
- Advances in Alzheimer's disease: mechanistic insights and therapeutic targets.Science China. Life sciences · 2026Review
- Scalable human neuronal models of tauopathy producing endogenous seed-competent 4R tau.Science advances · 2026Article
- Regulation of organic anion transporting polypeptide 1B1 transport function by lysine deacetylase 6.Molecular pharmacology · 2026Article
- First-in-human PET study of [Journal of translational medicine · 2026Article
- Biophysical assessment of the molecular mechanisms of Tau aggregation and its role in Alzheimer's disease.Protein science : a publication of the Protein Society · 2026Review
- Epigenetic Modulation Is a Key Mechanism in Cognitive Deficit: Unveiling Garcinol as a Potent HAT Inhibitor in Improving Alzheimer's Disease.ACS omega · 2026Review
- Cysteines are critical determinants of spontaneous and seeded tau aggregation in cells.Research square · 2026Article
- Cysteines are critical determinants of spontaneous and seeded tau aggregation in cells.bioRxiv : the preprint server for biology · 2026Article
- Sex-specific effects of acetylation on tauopathy in aging htau mice.Scientific reports · 2026Article
- HDAC6 Inhibition Reduces Seeded Tau and α-Synuclein Pathologies in Primary Neuron Cultures and Wild-Type Mice.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Article
- Atlas of lysine acetylation in the mouse.bioRxiv : the preprint server for biology · 2026Article
- Post-translational modifications as a regulatory code for tau function in health and disease.Frontiers in dementia · 2026Review
- Ethanol exposure and high-fat diet: assessing the neuroimmune and metabolic mechanisms in Alzheimer's disease pathology.Frontiers in neuroscience · 2026Review
- Tau protein: Physiological functions and multifaceted roles in neurodegenerative and psychiatric disorders.Genomic psychiatry : advancing science from genes to society · 2025Article
- Advances of therapeutic strategies for Alzheimer's disease.Journal of neurology · 2025Review
- Making tau amyloid models in vitro: a crucial and underestimated challenge.FEBS letters · 2025Review
- Single-Nucleus RNA Sequencing of HDAC6 Inhibition in Resolving Doxorubicin-Induced Cognitive Impairment.Molecular neurobiology · 2025Article
118 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
Abstract
The accumulation of hyperphosphorylated tau in neurofibrillary tangles (NFTs) is a neuropathological hallmark of tauopathies, including Alzheimer's disease (AD) and chronic traumatic encephalopathy, but effective therapies directly targeting the tau protein are currently lacking. Herein, we describe a novel mechanism in which the acetylation of tau on KXGS motifs inhibits phosphorylation on this same motif, and also prevents tau aggregation. Using a site-specific antibody to detect acetylation of KXGS motifs, we demonstrate that these sites are hypoacetylated in patients with AD, as well as a mouse model of tauopathy, suggesting that loss of acetylation on KXGS motifs renders tau vulnerable to pathogenic insults. Furthermore, we identify histone deacetylase 6 (HDAC6) as the enzyme responsible for the deacetylation of these residues, and provide proof of concept that acute treatment with a selective and blood-brain barrier-permeable HDAC6 inhibitor enhances acetylation and decreases phosphorylation on tau's KXGS motifs in vivo. As such, we have uncovered a novel therapeutic pathway that can be manipulated to block the formation of pathogenic tau species in disease.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.