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.

Physiological/pathological ramifications of transcription factors in the unfolded protein response

“…Neurodegenerative disease Developmental Xbp1 deletion in the murine nervous system protects dopaminergic neurons from 6-OHDA treatment (Valdes et al 2014), suggesting a pathogenic role for XBP1 in PD pathology. Therefore, a low-level UPR activation may produce an adaptive response during neuronal development to maintain protein homeostasis in the absence of XBP1 signaling.…”

“…In contrast, down-regulation of XBP1 expression in adult substantia nigra pars compacta (SNpc) induces strong ER stress that triggers massive dopaminergic neuron degeneration. In addition, delivery of XBP1s into the SNpc of adult mice protects dopaminergic neurons from 6-OHDA (Valdes et al 2014). Similar to PD, XBP1 suppresses Aβ neurotoxicity in the Drosophila eye and in cultured neurons by attenuating expression of the ryanodine receptor RyR3 to decrease Ca 2+ release into the cytosol (Casas-Tinto et al 2011).…”

ER stress in neurodegenerative disease: from disease mechanisms to therapeutic interventions

“…In agreement with this, treatment with non-lethal doses of tunicamycin in flies and mice models of PD provided protection against neurodegeneration [88]. Gene therapy to deliver XBP1 into the subtantia nigra of adult animals protected against neurodegeneration induced by PD-inducing neurotoxins [86,89]. This observation was also confirmed in a model where XBP1 is delivered to neuronal stem cells transferred to animals treated with rotenone [90].…”

“…Unexpectedly, genetic ablation of XBP1 throughout brain development increased neuronal resistance following 6-OHDA treatment, which was accompanied by the up-regulation of several UPR effectors in the substancia nigra, while there was no activation of pro-apoptotic UPR markers such as CHOP [86]. The concept of hormesis was proposed as the occurrence of mild ER stress may engage a protective program [1,87].…”

Link between endoplasmic reticulum stress and autophagy in neurodegenerative diseases

“…Furthermore, activating several UPR components, such as sXBP1, may also be beneficial. However, developmental ablation of XBP1 in the CNS was shown to cause resistance to 6-OHDA-induced neuronal death (51). Interestingly, the developmental ablation of XBP1 caused a compensatory upregulation of several other UPR components; this compensatory upregulation may cause a proteostatic alteration in order to resist stress (66).…”