Proceedings of the National Academy of Sciences - PNAS, 2014-03, Vol.111 (12), p.4584-4589
2014
Details
- Autor(en) / Beteiligte
- Titel
- Immunophilin FKBP52 induces Tau-P301L filamentous assembly in vitro and modulates its activity in a model of tauopathy
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2014-03, Vol.111 (12), p.4584-4589
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2014
- Link zum Volltext
- Quelle
- Elektronische Zeitschriftenbibliothek (Open access)
- Beschreibungen/Notizen
- The Tau protein is the major component of intracellular filaments observed in a number of neurodegenerative diseases known as tauopathies. The pathological mutant of Tau containing a proline-to-leucine mutation at position 301 (P301L) leads to severe human tauopathy. Here, we assess the impact of FK506-binding protein with a molecular mass of ∼52 kDa (FKBP52), an immunophilin protein that interacts with physiological Tau, on Tau-P301L activity. We identify a direct interaction of FKBP52 with Tau-P301L and its phosphorylated forms and demonstrate FKBP52's ability to induce the formation of Tau-P301L oligomers. EM analysis shows that Tau-P301L oligomers, induced by FKBP52, can assemble into filaments. In the transgenic zebrafish expressing the human Tau-P301L mutant, FKBP52 knockdown is sufficient to redrive defective axonal outgrowth and branching related to Tau-P301L expression in spinal primary motoneurons. This result correlates with a significant reduction of pT181 pathological phosphorylated Tau and with recovery of the stereotypic escape response behavior. Collectively, FKBP52 appears to be an endogenous candidate that directly interacts with the pathogenic Tau-P301L and modulates its function in vitro and in vivo.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.1402645111Titel-ID: cdi_hal_primary_oai_HAL_hal_01077897v1
- Format
- –
- Schlagworte
- Alzheimers disease, Animals, Animals, Genetically Modified, Antibodies, Biochemistry, Biochemistry, Molecular Biology, Biological Sciences, Biopolymers - metabolism, Cell Death - genetics, Cell Line, Danio rerio, Embryos, Gene Knockdown Techniques, Humans, In Vitro Techniques, Life Sciences, Models, Biological, Motor Neurons - metabolism, Mutation, Nervous system diseases, Neurodegenerative diseases, Neurological disorders, Neurons, Neuropathology, Oligomers, Pathology, Phosphorylation, Proteins, Stereotyped Behavior, Tacrolimus Binding Proteins - genetics, Tacrolimus Binding Proteins - metabolism, Tacrolimus Binding Proteins - physiology, Tau proteins, tau Proteins - metabolism, tau Proteins - physiology, Tauopathies, Tauopathies - pathology, Tauopathies - physiopathology, Zebrafish - physiology