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http://hdl.handle.net/10261/77257
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dc.contributor.author | López-Menéndez, Celia | es_ES |
dc.contributor.author | Gamir-Morralla, Andrea | es_ES |
dc.contributor.author | Jurado-Arjona, Jerónimo | es_ES |
dc.contributor.author | Higuero, Alonso M. | es_ES |
dc.contributor.author | Campanero, Miguel R. | es_ES |
dc.contributor.author | Ferrer, Isidro | es_ES |
dc.contributor.author | Hernández Pérez, Félix | es_ES |
dc.contributor.author | Ávila, Jesús | es_ES |
dc.contributor.author | Díaz-Guerra, Margarita | es_ES |
dc.contributor.author | Iglesias, Teresa | es_ES |
dc.date.accessioned | 2013-05-31T09:43:10Z | - |
dc.date.available | 2013-05-31T09:43:10Z | - |
dc.date.issued | 2013 | - |
dc.identifier | doi: 10.1093/hmg/dds446 | - |
dc.identifier | issn: 0964-6906 | - |
dc.identifier | e-issn: 1460-2083 | - |
dc.identifier.citation | Human Molecular Genetics 22(3): 466-482 (2013) | es_ES |
dc.identifier.uri | http://hdl.handle.net/10261/77257 | - |
dc.description.abstract | Failures in neurotrophic support and signalling play key roles in Alzheimer's disease (AD) pathogenesis. We previously demonstrated that downregulation of the neurotrophin effector Kinase D interacting substrate (Kidins220) by excitotoxicity and cerebral ischaemia contributed to neuronal death. This downregulation, triggered through overactivation of N-methyl-d-aspartate receptors (NMDARs), involved proteolysis of Kidins220 by calpain and transcriptional inhibition. As excitotoxicity is at the basis of AD aetiology, we hypothesized that Kidins220 might also be downregulated in this disease. Unexpectedly, Kidins220 is augmented in necropsies from AD patients where it accumulates with hyperphosphorylated tau. This increase correlates with enhanced Kidins220 resistance to calpain processing but no higher gene transcription. Using AD brain necropsies, glycogen synthase kinase 3-β (GSK3β)-transgenic mice and cell models of AD-related neurodegeneration, we show that GSK3β phosphorylation decreases Kidins220 susceptibility to calpain proteolysis, while protein phosphatase 1 (PP1) action has the opposite effect. As altered activities of GSK3β and phosphatases are involved in tau aggregation and constitute hallmarks in AD, a GSK3β/PP1 imbalance may also contribute to Kidins220 decreased clearance, accumulation and hampered neurotrophin signalling from early stages of the disease pathogenesis. These results encourage searches for mutations in Kidins220 gene and their possible associations to dementias. Finally, our data support a model where the effects of excitotoxicity drastically differ when occurring in cerebral ischaemia versus progressively sustained toxicity along AD progression. The striking differences in Kidins220 stability resulting from chronic versus acute brain damage may also have important implications for the therapeutic intervention of neurodegenerative disorders. © The Author 2012. Published by Oxford University Press. All rights reserved. | - |
dc.description.sponsorship | This work was supported by the Ministerio de Economía y Competitividad (SAF2011-26233 to T.I., BFU2010-18380/BFI to M.D.-G., SAF2010-15125 to M.R.C., SAF2006-02424 to F.H., SAF2010-15525 to J.A.); Comunidad de Madrid (P2010/BMD-2332-Neurodegmodels to T.I., F.H. and J.A.); and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas – CIBERNED, Instituto de Salud Carlos III, to T.I., F.H., J.A. and I.F. C.L.-M. is a recipient of a contract from SAF2011-26233; A.G.-M. has been funded by Noscira S.A. and a contract from P2010/BMD-2332; J.J.-A. is a recipient of a pre-doctoral fellowship/contract from Consejo Superior de Investigaciones Científicas and A.M.H. is a recipient of a contract from Hospital Nacional de Parapléjicos/Servicio de Salud de Castilla-La Mancha. | - |
dc.language.iso | eng | es_ES |
dc.publisher | Oxford University Press | es_ES |
dc.relation | S2010/BMD-2332-Neurodegmodels | - |
dc.rights | closedAccess | - |
dc.title | Kidins220 accumulates with tau in human Alzheimer's disease and related models: Modulation of its calpain-processing byGSK3β/PP1 imbalance | es_ES |
dc.type | artículo | es_ES |
dc.identifier.doi | 10.1093/hmg/dds446 | - |
dc.date.updated | 2013-05-31T09:43:10Z | - |
dc.description.version | Peer Reviewed | - |
dc.contributor.funder | Ministerio de Economía y Competitividad (España) | - |
dc.contributor.funder | Comunidad de Madrid | - |
dc.contributor.funder | Instituto de Salud Carlos III | - |
dc.contributor.funder | Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España) | - |
dc.contributor.funder | Consejo Superior de Investigaciones Científicas (España) | - |
dc.contributor.funder | Junta de Comunidades de Castilla-La Mancha | - |
dc.relation.csic | Sí | es_ES |
dc.identifier.funder | http://dx.doi.org/10.13039/501100003329 | es_ES |
dc.identifier.funder | http://dx.doi.org/10.13039/501100004587 | es_ES |
dc.identifier.funder | http://dx.doi.org/10.13039/501100003339 | es_ES |
dc.identifier.funder | http://dx.doi.org/10.13039/100012818 | es_ES |
dc.identifier.funder | http://dx.doi.org/10.13039/501100011698 | es_ES |
dc.type.coar | http://purl.org/coar/resource_type/c_6501 | es_ES |
item.languageiso639-1 | en | - |
item.fulltext | No Fulltext | - |
item.openairecristype | http://purl.org/coar/resource_type/c_18cf | - |
item.cerifentitytype | Publications | - |
item.grantfulltext | none | - |
item.openairetype | artículo | - |
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