Control of dopaminergic neuron survival by the unfolded protein response transcription factor XBP1.
Proc Natl Acad Sci U S A
; 111(18): 6804-9, 2014 May 06.
Article
in En
| MEDLINE
| ID: mdl-24753614
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Transcription Factors
/
DNA-Binding Proteins
/
Dopaminergic Neurons
Type of study:
Etiology_studies
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2014
Document type:
Article
Affiliation country: