ArticleThe Journal of biological chemistry2021
Myricetin slows liquid-liquid phase separation of Tau and activates ATG5-dependent autophagy to suppress Tau toxicity.
Article in The Journal of biological chemistry, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 72 citations in OpenAlex.
- A New Anatomy of Autophagic Clearance: On the Roles of Intrinsic Disorder in the Membrane-Less on Membrane-Encapsulated Mechanism.Membranes · 2026Review
- Protein Disulfide Isomerase Disassembles TDP-43/G3BP1 Condensates and Antagonizes TDP-43 Pathological Aggregates.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Targeting Liquid-Liquid Phase Separation and Autophagy in Alzheimer's Disease: Insights into Molecular Mechanisms and Therapeutic Potential.Neurochemical research · 2025Review
- The connection between autophagy and Alzheimer's disease.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2025Review
- Design and application of a Tau seed amplification assay for screening inhibitors of Tau seeding.Alzheimer's research & therapy · 2025Article
- Charged peptides enriched in aromatic residues decelerate condensate ageing driven by cross-β-sheet formation.Nature communications · 2025Article
- Rational Modulation of Liquid-Liquid Phase Separation Offers Novel Ways to Combat Tauopathies.International journal of molecular sciences · 2025Review
- The pathogenic APP N-terminal Val225Ala mutation alters tau protein liquid-liquid phase separation and exacerbates synaptic damage.Molecular psychiatry · 2025Article
- Myricetin Restores Autophagy to Attenuate Lumbar Intervertebral Disk Degeneration Via Negative Regulation of the JAK2/STAT3 Pathway.Biochemical genetics · 2025Article
- PhaSeDis: A Manually Curated Database of Phase Separation-disease Associations and Corresponding Small Molecules.Genomics, proteomics & bioinformatics · 2025Article
- Current perspectives in drug targeting intrinsically disordered proteins and biomolecular condensates.BMC biology · 2025Review
- Molecular insights into the effect of 1,6-hexanediol on FUS phase separation.The EMBO journal · 2025Article
- Liquid-liquid phase separation of Tau and α-synuclein: a new target for treating comorbidity in neurodegeneration.Biophysical reviews · 2025Review
- Plant-Based Inhibitors of Protein Aggregation.Biomolecules · 2025Review
- β-synuclein regulates the phase transitions and amyloid conversion of α-synuclein.Nature communications · 2024Article
- Biomolecular condensates and disease pathogenesis.Science China. Life sciences · 2024Review
- Tau liquid-liquid phase separation: At the crossroads of tau physiology and tauopathy.Journal of cellular physiology · 2024Review
- Construction of a cell-based aggregation and seeding model for the Tau protein.Acta biochimica et biophysica Sinica · 2024Article
- JunB condensation attenuates vascular endothelial damage under hyperglycemic condition.Journal of molecular cell biology · 2024Article
- Misfolded protein oligomers: mechanisms of formation, cytotoxic effects, and pharmacological approaches against protein misfolding diseases.Molecular neurodegeneration · 2024Review
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Intraneuronal neurofibrillary tangles composed of Tau aggregates have been widely accepted as an important pathological hallmark of Alzheimer's disease. A current therapeutic avenue for treating Alzheimer's disease is aimed at inhibiting Tau accumulation with small molecules such as natural flavonoids. Liquid-liquid phase separation (LLPS) of Tau can lead to its aggregation, and Tau aggregates can then be degraded by autophagy. However, it is unclear whether natural flavonoids modulate the formation of phase-separated Tau droplets or promote autophagy and Tau clearance. Here, using confocal microscopy and fluorescence recovery after photobleaching assays, we report that a natural antioxidant flavonoid compound myricetin slows LLPS of full-length human Tau, shifting the equilibrium phase boundary to a higher protein concentration. This natural flavonoid also significantly inhibits pathological phosphorylation and abnormal aggregation of Tau in neuronal cells and blocks mitochondrial damage and apoptosis induced by Tau aggregation. Importantly, using coimmunoprecipitation and Western blotting, we show that treatment of cells with myricetin stabilizes the interaction between Tau and autophagy-related protein 5 (ATG5) to promote clearance of phosphorylated Tau to indirectly limit its aggregation. Consistently, this natural flavonoid inhibits mTOR pathway, activates ATG5-dependent Tau autophagy, and almost completely suppresses Tau toxicity in neuronal cells. Collectively, these results demonstrate how LLPS and abnormal aggregation of Tau are inhibited by natural flavonoids, bridging the gap between Tau LLPS and aggregation in neuronal cells, and also establish that myricetin could act as an ATG5-dependent autophagic activator to ameliorate the pathogenesis of Alzheimer's disease.
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