Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 18, Pages 6804-6809Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1321845111
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Funding
- Michael J. Fox Foundation for Parkinson's Research
- Fondo de Fomento al Desarrollo Cientifico y Tecnologico [D11I1007]
- Millennium Institute [P09-015-F]
- Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT) [1140549]
- FONDECYT [3120146, 1110987]
- Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT) Capital Humano en la Academia [7912010006]
- Ring Initiative [ACT1109]
- Comite de Evaluacion y Orientacion de la Cooperacion Cientifica con Chile del Gobierno de Francia-CONICYT [C13S02]
- CONICYT [USA2013-0003, AT-24100179]
- Muscular Dystrophy Association
- ALS Therapy Alliance
- Alzheimer Association
- Millennium Nucleus [P07-011]
- Swiss National Science Foundation [31003A_135696]
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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.
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