AI Article Synopsis
- Stroke is a major health issue causing high rates of death and disability, and recent research highlights the role of Pin1, an enzyme that affects cell growth and apoptosis, in this context.
- In laboratory studies and mouse models, manipulating Pin1 levels showed that it enhances the stability of Notch1 intracellular domain (NICD1), leading to increased neuron death during ischemic conditions, while reducing Pin1 levels offered protection against stroke damage.
- The findings suggest that targeting Pin1 could be a potential new treatment strategy for ischemic stroke by inhibiting its role in promoting harmful cell signaling related to stroke-related neuron death.
Article Abstract
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.
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| http://dx.doi.org/10.1002/ana.24347 | DOI Listing |
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