Development of a neuroprotective peptide that preserves survival pathways by preventing Kidins220/ARMS calpain processing induced by excitotoxicity
Gamir-Morralla, A. (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)
López-Menéndez, C. (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)
Ayuso-Dolado, S. (Universidad Autónoma de Madrid. Instituto de Investigaciones Biomédicas "Alberto Sols")
Tejeda, G. S. (Universidad Autónoma de Madrid. Instituto de Investigaciones Biomédicas "Alberto Sols")
Montaner, J. (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Rosell, A. (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Iglesias, Tomás (Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas)
Díaz-Guerra, M. (Universidad Autónoma de Madrid. Instituto de Investigaciones Biomédicas "Alberto Sols")
Universitat Autònoma de Barcelona

Data:	2015
Resum:	Kinase D-interacting substrate of 220 kDa (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--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.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Cell death and disease, Vol. 6 (october 2015) , p. e1939, ISSN 2041-4889

DOI: 10.1038/cddis.2015.307
PMID: 26492372

12 p, 2.7 MB

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