ArticleMolecular psychiatry2023
Fyn nanoclustering requires switching to an open conformation and is enhanced by FTLD-Tau biomolecular condensates.
Article in Molecular psychiatry, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 20 citations in OpenAlex.
- Fyn kinase: a key mechanistic regulator and therapeutic target in tauopathy and neurodegenerative diseases.Translational neurodegeneration · 2026Review
- Article
- Liquid-liquid phase separation in neural development.Cellular and molecular life sciences : CMLS · 2026Review
- Fyn-Saracatinib Complex Structure Reveals an Active State-like Conformation.International journal of molecular sciences · 2026Article
- Single Particle Tracking Photo-Activated Localization Microscopy.Methods in molecular biology (Clifton, N.J.) · 2026Article
- From seeds to symptoms: the molecular landscape of tau seeding in Alzheimer's disease.Frontiers in neuroscience · 2026Review
- 5-HT6 receptors: Contemporary views on their neurobiological and pharmacological relevance in neuropsychiatric disorders.Dialogues in clinical neuroscience · 2025Review
- Nanoscale spatiotemporal cluster analysis of expressed and endogenous proteins.Nature protocols · 2025Review
- Fyn-dependent Tau microcluster formation seeds and boosts extensive Tau pathology.Acta neuropathologica · 2025Article
- Diverse influences on tau aggregation and implications for disease progression.Genes & development · 2025Review
- Article
- Updates in Alzheimer's disease: from basic research to diagnosis and therapies.Translational neurodegeneration · 2024Review
- Synapsin 2a tetramerisation selectively controls the presynaptic nanoscale organisation of reserve synaptic vesicles.Nature communications · 2024Article
- Location, location, location: Protein kinase nanoclustering for optimised signalling output.eLife · 2024Review
- Enhanced Fyn-tau and NR2B-PSD95 interactions in epileptic foci in experimental models and human epilepsy.Brain communications · 2024Article
- Development of small-molecule Tau-SH3 interaction inhibitors that prevent amyloid-β toxicity and network hyperexcitability.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2024Article
- Tau forms synaptic nano-biomolecular condensates controlling the dynamic clustering of recycling synaptic vesicles.Nature communications · 2023Article
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Fyn is a Src kinase that controls critical signalling cascades and has been implicated in learning and memory. Postsynaptic enrichment of Fyn underpins synaptotoxicity in dementias such as Alzheimer's disease and frontotemporal lobar degeneration with Tau pathology (FTLD-Tau). The FLTD P301L mutant Tau is associated with a higher propensity to undergo liquid-liquid phase separation (LLPS) and form biomolecular condensates. Expression of P301L mutant Tau promotes aberrant trapping of Fyn in nanoclusters within hippocampal dendrites by an unknown mechanism. Here, we used single-particle tracking photoactivated localisation microscopy to demonstrate that the opening of Fyn into its primed conformation promotes its nanoclustering in dendrites leading to increased Fyn/ERK/S6 downstream signalling. Preventing the auto-inhibitory closed conformation of Fyn through phospho-inhibition or through perturbation of its SH3 domain increased Fyn's nanoscale trapping, whereas inhibition of the catalytic domain had no impact. By combining pharmacological and genetic approaches, we demonstrate that P301L Tau enhanced both Fyn nanoclustering and Fyn/ERK/S6 signalling via its ability to form biomolecular condensates. Together, our findings demonstrate that Fyn alternates between a closed and an open conformation, the latter being enzymatically active and clustered. Furthermore, pathogenic immobilisation of Fyn relies on the ability of P301L Tau to form biomolecular condensates, thus highlighting the critical importance of LLPS in controlling nanoclustering and downstream intracellular signalling events.
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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 Socratic graph.