Control of dopaminergic neuron survival by the unfolded protein response transcription factor XBP1

Valdés P.; Mercado, G; Vidal, RL; Molina C.; Parsons, G; Court, FA; Martínez A; Galleguillos D; Armentano D.; Schneider, BL; Hetz C.

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.

Más información

Título según WOS: Control of dopaminergic neuron survival by the unfolded protein response transcription factor XBP1
Título según SCOPUS: Control of dopaminergic neuron survival by the unfolded protein response transcription factor XBP1
Título de la Revista: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volumen: 111
Número: 18
Editorial: NATL ACAD SCIENCES
Fecha de publicación: 2014
Página de inicio: 6804
Página final: 6809
Idioma: English
DOI:

10.1073/pnas.1321845111

Notas: ISI, SCOPUS