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dc.contributor.authorLabrador-Garrido, Adahir-
dc.contributor.authorCejudo-Guillén, Marta-
dc.contributor.authorLeal, María M.-
dc.contributor.authorKlippstein, Rebecca-
dc.contributor.authorVilladiego, Javier-
dc.contributor.authorToledo-Aral, Juan José-
dc.contributor.authorDobson, Christopher M.-
dc.contributor.authorPozo, David-
dc.contributor.authorRoodveldt, Cintia-
dc.identifierdoi: 10.1096/fj.15-275131-
dc.identifierissn: 0892-6638-
dc.identifiere-issn: 1530-6860-
dc.identifier.citationFASEB Journal 30(2): 564-577 (2016)-
dc.descriptionLabrador-Garrido, Adahir et al.-
dc.description.abstractWe have investigated the potential role of molecular chaperones as modulators of the immune response by using α-synuclein (αSyn) as an aggregation-prone model protein. We first performed an in vitro immunoscreening with 21 preselected candidate chaperones and selected 2 from this set as displaying immunological activity with differential profiles, Grp94/Gp96 and FKBP4/52. We then immunized mice with both chaperone/α-synuclein combinations using monomeric or oligomeric α-synuclein (MαSyn or OαSyn, respectively), and we characterized the immune response generated in each case. We found that Grp94 promoted αSyn-specific T-helper (Th)1/Th17 and IgG1 antibody responses (up to a 3-fold increase) with MαSyn and OαSyn, respectively, coupled to a Th2-type general phenotype (generating 2.5-fold higher IgG1/IgG2 levels). In addition, we observed that FKBP4 favored a Th1-skewed phenotype with MαSyn but strongly supported a Th2-type phenotype with OαSyn (with a 3-fold higher IL-10/IFN-γ serum levels). Importantly, results from adoptive transfer of splenocytes from immunized animals in a Parkinson’s disease mouse model indicates that these effects are robust, stable in time, and physiologically relevant. Taken together, Grp94 and FKBP4 are able to generate differential immune responses to α-synuclein–based immunizations, depending both on the nature of the chaperone and on the aggregation state of α-synuclein. Our work reveals that several chaperones are potential modulators of the immune response and suggests that different chaperones could be exploited to redirect the amyloid-elicited immunity both for basic studies of the immunological processes associated with neurodegeneration and for immunotherapy of pathologies associated with protein misfolding and aggregation.-
dc.description.sponsorshipFinancial support was provided by the Carlos III Institute of Health of Spain (Spanish Ministry of Economy and Competitiveness) according to the Strategic Action of Health (CP10/00527 to C.R.; PI14-01600 to D.P.), with cofunding by Fonds Europeen de Developpement Economique et Regional (FEDER) funds, from the Spanish Ministry of Economy and Competitiveness (SAF-2012/39720 to C.R.) with cofunding by FEDER funds, the Andalusian Ministry of Economy, Science and Innovation (P10-CTS-6928 and P11-CTS-8161 to D.P.), and the Andalusian Plan for Research, Development and Innovation (PAIDI) Program from the Andalusian Government (CTS-677 to D.P.). A.L.G. holds a Formacion del Profesorado Universitario (FPU) Pre-doctoral Fellowship from the Spanish Ministry of Education (AP-2009/3816). The work of E.J.D.G. and C.M.D. is supported by the Wellcome Trust, the Medical Research Council, and the Biotechnology and Biological Sciences Research Council of the United Kingdom.-
dc.publisherFederation of American Societies for Experimental Biology-
dc.subjectHeatshock protein-
dc.subjectMisfolding/amyloid disease-
dc.titleChaperome screening leads to identification of Grp94/Gp96 and FKBP4/52 as modulators of the α-synuclein-elicited immune response-
dc.description.versionPeer Reviewed-
dc.contributor.funderMinisterio de Economía y Competitividad (España)-
dc.contributor.funderInstituto de Salud Carlos III-
dc.contributor.funderEuropean Commission-
dc.contributor.funderJunta de Andalucía-
dc.contributor.funderMinisterio de Educación, Cultura y Deporte (España)-
dc.contributor.funderBiotechnology and Biological Sciences Research Council (UK)-
dc.contributor.funderMedical Research Council (UK)-
dc.contributor.funderWellcome Trust-
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