Control of dopaminergic neuron survival by the unfolded protein response transcription factor XBP1
Author | dc.contributor.author | Valdés, Pamela | |
Author | dc.contributor.author | Mercado, Gabriela | es_CL |
Author | dc.contributor.author | Vidal, René L. | es_CL |
Author | dc.contributor.author | Molina, Claudia | es_CL |
Author | dc.contributor.author | Parsons, Geoffrey | es_CL |
Author | dc.contributor.author | Court, Felipe A. | es_CL |
Author | dc.contributor.author | Martínez, Alexis | es_CL |
Author | dc.contributor.author | Galleguillos, Danny | es_CL |
Author | dc.contributor.author | Armentano, Donna | es_CL |
Author | dc.contributor.author | Schneider, Bernard L. | es_CL |
Author | dc.contributor.author | Hetz Flores, Claudio | es_CL |
Admission date | dc.date.accessioned | 2014-12-18T17:48:39Z | |
Available date | dc.date.available | 2014-12-18T17:48:39Z | |
Publication date | dc.date.issued | 2014 | |
Cita de ítem | dc.identifier.citation | PNAS | May 6, 2014 | vol. 111 | no. 18 | en_US |
Identifier | dc.identifier.other | DOI: 10.1073/pnas.1321845111 | |
Identifier | dc.identifier.uri | https://repositorio.uchile.cl/handle/2250/129424 | |
General note | dc.description | Artículo de publicación ISI | en_US |
Abstract | dc.description.abstract | Parkinson disease (PD) is characterized by the selective loss of dopaminergic neurons of the substantia nigra pars compacta (SNpc). Although growing evidence indicates that endoplasmic reticulum (ER) stress is a hallmark of PD, its exact contribution to the disease process is not well understood. Here we report that developmental ablation of X-Box binding protein 1 (XBP1) in the nervous system, a key regulator of the unfolded protein response (UPR), protects dopaminergic neurons against a PD-inducing neurotoxin. This survival effect was associated with a preconditioning condition that resulted from induction of an adaptive ER stress response in dopaminergic neurons of the SNpc, but not in other brain regions. In contrast, silencing XBP1 in adult animals triggered chronic ER stress and dopaminergic neuron degeneration. Supporting this finding, gene therapy to deliver an active form of XBP1 provided neuroprotection and reduced striatal denervation in animals injected with 6-hydroxydopamine. Our results reveal a physiological role of the UPR in the maintenance of protein homeostasis in dopaminergic neurons that may help explain the differential neuronal vulnerability observed in PD. | en_US |
Patrocinador | dc.description.sponsorship | This work was funded primarily by the Michael J. Fox Foundation for Parkinson’s Research, Fondo de Fomento al Desarrollo Científico y Tecnológico D11I1007, Millennium Institute P09-015-F, Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT) 1140549 (to C.H.), FONDECYT 3120146 (to G.M.), Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) Capital Humano en la Academia 7912010006 (to R.L.V.), and Ring Initiative ACT1109 (to C.H. and F.A.C.). Funding was also provided by Comité de Evaluación y Orientación de la Cooperación Científica con Chile del Gobierno de Francia-CONICYT C13S02, CONICYT Grant USA2013-0003, the Muscular Dystrophy Association, the ALS Therapy Alliance, and the Alzheimer Association (C.H.). P.V., C.M., and A.M. are doctoral fellows supported by a CONICYT fellowship and CONICYT Research Grant AT- 24100179). F.A.C. is supported by FONDECYT 1110987 and Millennium Nucleus P07-011-F. B.L.S. is supported by the Swiss National Science Foundation (Grant 31003A_135696). | en_US |
Lenguage | dc.language.iso | en | en_US |
Publisher | dc.publisher | CrossMark | en_US |
Type of license | dc.rights | Attribution-NonCommercial-NoDerivs 3.0 Chile | * |
Link to License | dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/cl/ | * |
Título | dc.title | Control of dopaminergic neuron survival by the unfolded protein response transcription factor XBP1 | en_US |
Document type | dc.type | Artículo de revista |
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