The ER stress factor XBP1s prevents amyloid-β neurotoxicity

Abstract

Alzheimer's disease (AD) is an incurable neurodegenerative disorder clinically characterized by progressive cognitive impairment. A prominent pathologic hallmark in the AD brain is the abnormal accumulation of the amyloid-β 1-42 peptide (Aβ), but the exact pathways mediating Aβ neurotoxicity remain enigmatic. Endoplasmic reticulum (ER) stress is induced during AD, and has been indirectly implicated as a mediator of Aβ neurotoxicity. We report here that Aβ activates the ER stress response factor X-box binding protein 1 (XBP1) in transgenic flies and in mammalian cultured neurons, yielding its active form, the transcription factor XBP1s. XBP1s shows neuroprotective activity in two different AD models, flies expressing Aβ and mammalian cultured neurons treated with Aβ oligomers. Trying to identify the mechanisms mediating XBP1s neuroprotection, we found that in PC12 cells treated with Aβ oligomers, XBP1s prevents the accumulation of free calcium (Ca(2+)) in the cytosol. This protective activity can be mediated by the downregulation of a specific isoform of the ryanodine Ca(2+) channel, RyR3. In support of this observation, a mutation in the only ryanodine receptor (RyR) in flies also suppresses Aβ neurotoxicity, indicating the conserved mechanisms between the two AD models. These results underscore the functional relevance of XBP1s in Aβ toxicity, and uncover the potential of XBP1 and RyR as targets for AD therapeutics.

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

“…XBP1 is one of the main downstream components of IRE1 mediating proteostasis adjustment, promoting cell survival. In agreement with this concept, expression of active XBP1s in transgenic flies expressing amyloid β prevented neuronal loss [44]. Consistent with this, brain samples from AD patients presented augmented XBP1 [41].…”

Proteostasis impairment in protein-misfolding and -aggregation diseases

“…Induction of the ER stress factor XBP1s can even prevent amyloid-β neurotoxicity in model systems for AD [93]. Phramacologically prolonging the transient attenuation of translation that occurs upon ER stress may be employed to adjust protein production rates to levels manageable by available chaperones [94].…”

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

“…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). Xbp1 deletion delays progression of Huntington's disease (HD) by increasing autophagy to degrade the mutant Huntingtin (Htt) protein.…”