Abstract
Reelin is an extracellular glycoprotein involved in key cellular processes in developing and adult nervous system, including regulation of neuronal migration, synapse formation, and plasticity. Most of these roles are mediated by the intracellular phosphorylation of disabled-1 (Dab1), an intracellular adaptor molecule, in turn mediated by binding Reelin to its receptors. Altered expression and glycosylation patterns of Reelin in cerebrospinal and cortical extracts have been reported in Alzheimer’s disease. However, putative changes in Reelin are not described in natural prionopathies or experimental models of prion infection or toxicity. With this is mind, in the present study, we determined that Reelin protein and mRNA levels increased in CJD human samples and in mouse models of human prion disease in contrast to murine models of prion infection. However, changes in Reelin expression appeared only at late terminal stages of the disease, which prevent their use as an efficient diagnostic biomarker. In addition, increased Reelin in CJD and in in vitro models does not correlate with Dab1 phosphorylation, indicating failure in its intracellular signaling. Overall, these findings widen our understanding of the putative changes of Reelin in neurodegeneration.
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Acknowledgments
The authors thank Tom Yohannan for the editorial advice and M. Segura-Feliu for the technical assistance. We thank members of the Del Río, Torres, Requena, Zerr and Ferrer groups for stimulating discussions and ideas. We thank members of José Luis Labandeira laboratory (CIMUS) for helping us with the histological processing of the inoculated mice. We also thank Eduardo Soriano for the gift of the reeler mice and Tom Curran for the gift of the Reln in situ probe. This research was supported by grants from the Spanish Ministry of Economy and Competitiveness (MINECO) (BFU2015-67777-R and TEC2015-72718-EXP), the Spanish prion network (Prionet Spain, AGL2015-71764-REDT), the Generalitat de Catalunya (SGR2014-1218), CIBERNED (PI2014/02-4 (Rapid dementias) and PRY-14-114), and La Caixa Obra Social Foundation, La Marató de TV3 to JADR. R.G. was supported by Fondo de Investigaciones Sanitarias (FIS, PI11-00075). I.F. was funded by the Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III—Fondos FEDER, a way to build Europe FIS grants PI14/00757, and CIBERNED (PI2014/02-4). JM.T. was supported by Spanish Ministry Economy and Competitiveness (RTA2012-00004 and AGL2012-37988-C04 projects). J.R.R. was supported by a grant from the Spanish Ministry of Economy and Competitiveness (MINECO) (BFU2013-48436-C2-1-P). I.Z. received support by the Robert-Koch-Institute through funds of Federal Ministry of Health (grant no. 1369-341) and DZNE (German Center for Neurodegenerative Diseases). A.M. was supported by a fellowship from the Spanish Ministry of Economy and Competitiveness. S.V was supported by a Juan de la Cierva contract of the Spanish Ministry of Science and Innovation (MICIM).
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All experiments were performed under the guidelines and protocols of the Ethical Committee for Animal Experimentation (CEEA) of the University of Barcelona, and the protocol for the use of animals in this study was reviewed and approved by the CEEA of the University of Barcelona (CEEA approval no. 276/16 and 141/15).
Experiments were approved by the Committee on the Ethics of Animal Experiments of the author’s institutions (INIA and INRA; and University of Santiago de Compostela, 15005AE/12/FUN01/PAT05/JRR3).
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Agata Mata and Laura Urrea contributed equally to this study.
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Fig S1
Determination of PrPC expression in primary cortical neurons at different DIVs. (JPEG 1190 kb)
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Mata, A., Urrea, L., Vilches, S. et al. Reelin Expression in Creutzfeldt-Jakob Disease and Experimental Models of Transmissible Spongiform Encephalopathies. Mol Neurobiol 54, 6412–6425 (2017). https://doi.org/10.1007/s12035-016-0177-8
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DOI: https://doi.org/10.1007/s12035-016-0177-8