PIKfyve activity is required for lysosomal trafficking of tau aggregates and tau seeding
| Autor: | Alberto Carpinteiro Soares, Jonas Mariën, Edward B. Lee, John Q. Trojanowski, Charlotte Delay, Andreia Ferreira, Dieder Moechars, Louis De Muynck, Wim Annaert |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Endosome Endocytic cycle RAC1 tau Proteins tau uptake Biochemistry Hippocampus Protein Aggregation Pathological 03 medical and health sciences PIKFYVE Mice Phosphatidylinositol 3-Kinases PFF preformed fibril AF488 Alexa Fluor 488 mental disorders medicine Animals HSPG heparan sulfate proteoglycan Molecular Biology Actin Neurons 030102 biochemistry & molecular biology Chemistry Disease progression tauopathy A protein food and beverages PHF paired helical filament Cell Biology Editors' Pick Alzheimer's disease tau seeding medicine.disease PIKfyve Cell biology Mice Inbred C57BL Protein Transport 030104 developmental biology Tauopathies MVB multivesicular body DN dominant negative Tauopathy AD Alzheimer's disease Lysosomes Rac1 Research Article |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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