title: Control of dopaminergic neuron survival by the unfolded protein response transcription factor XBP1.
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.
authors.affiliation: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago 8380453, Chile.
authors.forename: Pamela
authors.initials: P
authors.lastname: Valdés
authors.forename: Gabriela
authors.initials: G
authors.lastname: Mercado
authors.forename: Rene L
authors.initials: RL
authors.lastname: Vidal
authors.forename: Claudia
authors.initials: C
authors.lastname: Molina
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Parsons
authors.forename: Felipe A
authors.initials: FA
authors.lastname: Court
authors.forename: Alexis
authors.initials: A
authors.lastname: Martinez
authors.forename: Danny
authors.initials: D
authors.lastname: Galleguillos
authors.forename: Donna
authors.initials: D
authors.lastname: Armentano
authors.forename: Bernard L
authors.initials: BL
authors.lastname: Schneider
authors.forename: Claudio
authors.initials: C
authors.lastname: Hetz
mesh_terms: D000818:Animals; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration; D009498:Neurotoxins / Q000633:toxicity; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D000071701:Regulatory Factor X Transcription Factors; D013378:Substantia Nigra / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D009498:Neurotoxins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; D016627:Oxidopamine
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