The ER stress factor XBP1s prevents amyloid-β neurotoxicity

被引:227
作者
Casas-Tinto, Sergio [1 ,2 ]
Zhang, Yan [1 ,2 ]
Sanchez-Garcia, Jonatan [2 ]
Gomez-Velazquez, Melisa [1 ]
Rincon-Limas, Diego E. [1 ,2 ]
Fernandez-Funez, Pedro [1 ,2 ,3 ]
机构
[1] Univ Texas Med Branch, Dept Neurol, Galveston, TX 77555 USA
[2] Univ Florida, McKnight Brain Inst, Dept Neurol, Gainesville, FL 32610 USA
[3] Univ Florida, McKnight Brain Inst, Dept Neurosci, Gainesville, FL 32610 USA
关键词
UNFOLDED-PROTEIN RESPONSE; ENDOPLASMIC-RETICULUM STRESS; AMYOTROPHIC-LATERAL-SCLEROSIS; KNOCK-IN MICE; ALZHEIMERS-DISEASE; RYANODINE RECEPTOR; CALCIUM-RELEASE; RETINAL DEGENERATION; TRANSCRIPTION FACTOR; PRION REPLICATION;
D O I
10.1093/hmg/ddr100
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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-beta 1-42 peptide (A beta), but the exact pathways mediating A beta neurotoxicity remain enigmatic. Endoplasmic reticulum (ER) stress is induced during AD, and has been indirectly implicated as a mediator of A beta neurotoxicity. We report here that A beta 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 A beta and mammalian cultured neurons treated with A beta oligomers. Trying to identify the mechanisms mediating XBP1s neuroprotection, we found that in PC12 cells treated with A beta oligomers, XBP1s prevents the accumulation of free calcium (Ca2+) in the cytosol. This protective activity can be mediated by the downregulation of a specific isoform of the ryanodine Ca2+ channel, RyR3. In support of this observation, a mutation in the only ryanodine receptor (RyR) in flies also suppresses A beta neurotoxicity, indicating the conserved mechanisms between the two AD models. These results underscore the functional relevance of XBP1s in A beta toxicity, and uncover the potential of XBP1 and RyR as targets for AD therapeutics.
引用
收藏
页码:2144 / 2160
页数:17
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