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Título

Brain ischaemia induces shedding of a BDNF-scavenger ectodomain from TrkB receptors by excitotoxicity activation of metalloproteinases and γ-secretases

AutorTejeda, Gonzalo S.; Ayuso Dolado, Sara; Arbeteta, Raquel; Esteban-Ortega, Gema M.; Vidaurre, Oscar G.; Díaz-Guerra, Margarita
Palabras claveTrkB
Excitotoxicity
Metalloproteinases
γ-secretases
Stroke
Ischaemia
Fecha de publicación2016
EditorJohn Wiley & Sons
CitaciónJournal of Pathology 238(5): 627-640 (2016)
ResumenStroke remains a leading cause of death and disability in the world with limited therapies available to restrict brain damage or improve functional recovery after cerebral ischaemia. A promising strategy currently under investigation is the promotion of brain-derived neurotrophic factor (BDNF)-signalling through tropomyosin-related kinase B (TrkB) receptors; a pathway essential for neuronal survival and function. However, TrkB and BDNF-signalling are impaired by excitotoxicity, a primary pathological process in stroke also associated with neurodegenerative diseases. Pathological imbalance of TrkB isoforms is critical in neurodegeneration and is caused by calpain-processing of BDNF high affinity full-length receptor (TrkB-FL) and an inversion of the transcriptional pattern of the Ntrk2 gene, to favour expression of the truncated isoform TrkB-T1 over TrkB-FL. We report here that both TrkB-FL and neuronal TrkB-T1 also undergo ectodomain shedding by metalloproteinases activated after ischemic injury or excitotoxic damage of cortical neurons. Subsequently, the remaining membrane-bound C-terminal fragments (CTFs) are cleaved by ¿-secretases within the transmembrane region, releasing their intracellular domains (ICDs) into the cytosol. Therefore, we identify TrkB-FL and TrkB-T1 as new substrates of regulated intramembrane proteolysis (RIP), a mechanism that highly contributes to TrkB-T1 regulation in ischaemia but is minor for TrkB-FL which is mainly processed by calpain. However, since the secreted TrkB ectodomain acts as a BDNF-scavenger and significantly alters BDNF/TrkB-signalling, the mechanism of RIP could contribute to neuronal death in excitotoxicity. These results are highly relevant since they reveal new targets for the rational design of therapies to treat stroke and other pathologies with an excitotoxic component.
Versión del editorhttps://doi.org/10.1002/path.4684
URIhttp://hdl.handle.net/10261/151157
DOI10.1002/path.4684
Identificadoresdoi: 10.1002/path.4684
e-issn: 1096-9896
issn: 0022-3417
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