Web of Science: 19 cites, Scopus: 19 cites, Google Scholar: cites,
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, T (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. Creative Commons
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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 Registre creat el 2018-01-31, darrera modificació el 2022-01-17



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