ArticleThe Journal of biological chemistry
PIKfyve activity is required for lysosomal trafficking of tau aggregates and tau seeding.
Article in The Journal of biological chemistry. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 41 citations in OpenAlex.
- Synthesis and evaluation of 3,5-disubstituted isothiazolo[4,5-b]pyridines, pyrazolo[4,3-b]pyridines and isothiazolo[3,4-b]pyrazines as inhibitors of PIKfyve.Bioorganic chemistry · 2026Article
- Sex- and brain region-specific gene expression in Alzheimer's disease.Journal of Alzheimer's disease : JAD · 2026Article
- Article
- LAMP1 and LAMP2A localise to axonal organelles with distinct motility dynamics and partially overlapping molecular signatures in human neurons.Journal of cell science · 2026Article
- Disruption of the PIKfyve complex unveils an adaptive mechanism to promote lysosomal repair and mitochondrial homeostasis.Nature communications · 2025Article
- Tau seeding in neurons enabled by transient endolysosomal perforations are confined within endolysosomes.bioRxiv : the preprint server for biology · 2025Article
- Physiological roles of phosphoinositides and inositol phosphates: Implications for metabolic dysfunction-associated steatotic liver disease.Clinical science (London, England : 1979) · 2025Review
- Structure-Activity Relationship Study of 3-Alkynyl-6-aryl-isothiazolo[4,3-Pharmaceuticals (Basel, Switzerland) · 2025Article
- Heavy metal-induced disruption of the autophagy-lysosomal pathway: implications for aging and neurodegenerative disorders.Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine · 2025Review
- A PIKfyve modulator combined with an integrated stress response inhibitor to treat lysosomal storage diseases.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Review
- Article
- Anti-tau intrabodies: From anti-tau immunoglobulins to the development of functional scFv intrabodies.Molecular therapy. Methods & clinical development · 2023Article
- Lysosomes in senescence and aging.EMBO reports · 2023Review
- PIP5K1C phosphoinositide kinase deficiency distinguishes PIKFYVE-dependent cancer cells from non-malignant cells.Autophagy · 2023Article
- Beyond PI3Ks: targeting phosphoinositide kinases in disease.Nature reviews. Drug discovery · 2023Review
- The synthetic TRPML1 agonist ML-SA1 rescues Alzheimer-related alterations of the endosomal-autophagic-lysosomal system.Journal of cell science · 2023Article
- Article
- PIP kinases: A versatile family that demands further therapeutic attention.Advances in biological regulation · 2023Article
- The 3-O sulfation of heparan sulfate proteoglycans contributes to the cellular internalization of tau aggregates.BMC molecular and cell biology · 2022Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
Tauopathies, such as Alzheimer's disease (AD), are neurodegenerative disorders characterized by the deposition of hyperphosphorylated tau aggregates. Proteopathic tau seeds spread through the brain in a temporospatial pattern, indicative of transsynaptic propagation. It is hypothesized that reducing the uptake of tau seeds and subsequent induction of tau aggregation could be a potential approach for abrogating disease progression in AD. Here, we studied to what extent different endosomal routes play a role in the neuronal uptake of preformed tau seeds. Using pharmacological and genetic tools, we identified dynamin-1, actin, and Rac1 as key players. Furthermore, inhibition of PIKfyve, a protein downstream of Rac1, reduced both the trafficking of tau seeds into lysosomes and the induction of tau aggregation. Our work shows that tau aggregates are internalized by a specific endocytic mechanism and that their fate once internalized can be pharmacologically modulated to reduce tau seeding in neurons.
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Registered trials
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.