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

Tejeda, G. S. , Ayuso-Dolado, S., Arbeteta, R., Esteban-Ortega, G. M., Vidaurre, O. G. and Díaz-Guerra, M. (2016) Brain ischaemia induces shedding of a BDNF-scavenger ectodomain from TrkB receptors by excitotoxicity activation of metalloproteinases and γ-secretases. Journal of Pathology, 238(5), pp. 627-640. (doi: 10.1002/path.4684) (PMID:26712630)

Full text not currently available from Enlighten.

Abstract

Stroke 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 ischaemic injury or excitotoxic damage of cortical neurons. Subsequently, the remaining membrane‐bound C‐terminal fragments (CTFs) are cleaved by γ‐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.

Item Type:Articles
Additional Information:This work was supported by the Ministerio deEconomía y Competitividad (BFU2010-18380/BFI andBFU2013-43808-R) and Fundación Mutua Madrileña(reference No 201322001). GST was funded by con-tracts from projects BFU2010-18380/BFI, FundaciónMutua Madrileña and BFU2013-43808-R. SA-D is arecipient of a FPI pre-doctoral fellowship associatedwith BFU2010-18380/BFI. GME-O is funded by acontract associated with project BFU2013-43808-R.The cost of this publication has been paid in part byFEDER funds. We thank Drs S Lorrio, JM Cosgaya, TIglesias, and J Renart for technical advice and helpfuldiscussions.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Tejeda, Dr Gonzalo
Authors: Tejeda, G. S., Ayuso-Dolado, S., Arbeteta, R., Esteban-Ortega, G. M., Vidaurre, O. G., and Díaz-Guerra, M.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Journal of Pathology
Publisher:Wiley
ISSN:0022-3417
ISSN (Online):1096-9896
Published Online:24 February 2016

University Staff: Request a correction | Enlighten Editors: Update this record