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P in1 promotes neuronal death in stroke by stabilizing N otch intracellular domain
Author(s) -
Baik SangHa,
Fane Mitchell,
Park Joon Hyung,
Cheng YiLin,
YangWei Fann David,
Yun Ui Jeong,
Choi Yuri,
Park JongSung,
Chai Bing Han,
Park Jin Su,
Back Seung Hyun,
Jeong Jae In,
Jang Ye Jin,
Bahn Gahee,
Lee JooYong,
Li YuI,
Sobey Christopher G.,
Uchida Takafumi,
Park Jae Hyung,
Kim Hong Tae,
Tang SungChun,
Arumugam Thiruma V.,
Jo DongGyu
Publication year - 2015
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.24347
Subject(s) - pin1 , neuroprotection , programmed cell death , intracellular , pharmacology , apoptosis , stroke (engine) , microbiology and biotechnology , chemistry , cancer research , medicine , biology , biochemistry , isomerase , enzyme , mechanical engineering , engineering
Objective Stroke is a leading cause of mortality and disability. The peptidyl‐prolyl cis / trans isomerase Pin1 regulates factors involved in cell growth. Recent evidence has shown that Pin1 plays a major role in apoptosis. However, the role of Pin1 in ischemic stroke remains to be investigated. Methods We used Pin1 overexpression and knockdown to manipulate Pin1 expression and explore the effects of Pin1 in cell death on ischemic stress in vitro and in a mouse stroke model. We also used Pin 1 inhibitor, γ‐secretase inhibitor, Notch1 intracellular domain (NICD1)‐deleted mutant cells, and Pin1 mutant cells to investigate the underlying mechanisms of Pin1‐NICD1–mediated cell death. Results Our findings indicate that Pin1 facilitates NICD1 stability and its proapoptotic function following ischemic stroke. Thus, overexpression of Pin1 increased NICD1 levels and enhanced its potentiation of neuronal death in simulated ischemia. By contrast, depletion or knockout of Pin1 reduced the NICD1 level, which in turn desensitized neurons to ischemic conditions. Pin1 interacted with NICD1 and increased its stability by inhibiting FBW7‐induced polyubiquitination. We also demonstrate that Pin1 and NICD1 levels increase following stroke. Pin1 heterozygous (+/−) and knockout (−/−) mice, and also wild‐type mice treated with an inhibitor of Pin1, each showed reduced brain damage and improved functional outcomes in a model of focal ischemic stroke. Interpretation These results suggest that Pin1 contributes to the pathogenesis of ischemic stroke by promoting Notch signaling, and that inhibition of Pin1 is a novel approach for treating ischemic stroke. Ann Neurol 2015;77:504–516