2024-03-29T00:16:50Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1543272022-09-23T10:14:18Zcom_10261_22com_10261_1col_10261_275
Development of a neuroprotective peptide that preserves survival pathways by preventing Kidins220/ARMS calpain processing induced by excitotoxicity
Gamir-Morralla, Andrea
López-Menéndez, Celia
Ayuso Dolado, Sara
Tejeda, Gonzalo S.
Montaner, J.
Iglesias, Teresa
Díaz-Guerra, Margarita
Consejo Superior de Investigaciones Científicas (España)
Instituto de Salud Carlos III
Ministerio de Economía y Competitividad (España)
Comunidad de Madrid
Kinase D-interacting substrate of 220kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning (ARMS), has a central role in the coordination of receptor crosstalk and the integration of signaling pathways essential for neuronal differentiation, survival and function. This protein is a shared downstream effector for neurotrophin- and ephrin-receptors signaling that also interacts with the N-methyl-d-aspartate type of glutamate receptors (NMDARs). Failures in neurotrophic support and glutamate signaling are involved in pathologies related to excitotoxicity and/or neurodegeneration, where different components of these dynamic protein complexes result altered by a combination of mechanisms. In the case of Kidins220/ARMS, overactivation of NMDARs in excitotoxicity and cerebral ischemia triggers its downregulation, which contributes to neuronal death. This key role in neuronal life/death decisions encouraged us to investigate Kidins220/ARMS as a novel therapeutic target for neuroprotection. As the main mechanism of Kidins220/ARMS downregulation in excitotoxicity is proteolysis by calpain, we decided to develop cell-penetrating peptides (CPPs) that could result in neuroprotection by interference of this processing. To this aim, we first analyzed in detail Kidins220/ARMS cleavage produced in vitro and in vivo, identifying a major calpain processing site in its C-terminal region (between amino acids 1669 and 1670) within a sequence motif highly conserved in vertebrates. Then, we designed a 25-amino acids CPP (Tat-K) containing a short Kidins220/ARMS sequence enclosing the identified calpain site (amino acids 1668-1681) fused to the HIV-1 Tat protein basic domain, able to confer membrane permeability to attached cargoes. Transduction of cortical neurons with Tat-K reduced Kidins220/ARMS calpain processing in a dose- and time-dependent manner upon excitotoxic damage and allowed preservation of the activity of pERK1/2 and pCREB, signaling molecules central to neuronal survival and functioning. Importantly, these effects were associated to a significant increase in neuronal viability. This Kidins220/ARMS-derived peptide merits further research to develop novel neuroprotective therapies for excitotoxicity-associated pathologies.
2017-08-23T11:49:49Z
2017-08-23T11:49:49Z
2015
2017-08-23T11:49:50Z
artículo
Cell Death and Disease 6(10): e1939 (2015)
http://hdl.handle.net/10261/154327
10.1038/cddis.2015.307
http://dx.doi.org/10.13039/501100003329
http://dx.doi.org/10.13039/501100003339
http://dx.doi.org/10.13039/501100004587
http://dx.doi.org/10.13039/100012818
26492372
eng
Publisher's version
https://doi.org/10.1038/cddis.2015.307
Sí
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/BFU2013-43808-R
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2014-52737-P
S2010/BMD-2331/NEURODEGMODELS
http://creativecommons.org/licenses/by/4.0/
openAccess
Nature Publishing Group