<br>线粒体相关内质网膜束缚蛋白 VAPB-PTPIP51 通过抑制自噬激活预防缺血性中风,CNS Neuroscience & Therapeutics

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线粒体相关内质网膜束缚蛋白 VAPB-PTPIP51 通过抑制自噬激活预防缺血性中风
CNS Neuroscience & Therapeutics ( IF 4.8 ) Pub Date : 2024-04-08 , DOI: 10.1111/cns.14707
Mingyang Li ₁ , Yonggang Zhang ₁ , Guixiang Yu ₂ , Lijuan Gu ₃ , Hua Zhu ₁ , Shi Feng ₁ , Xiaoxing Xiong _{1,

3} , Zhihong Jian ₁

Affiliation

目的线粒体相关内质网膜（MAM）是连接细胞内内质网（ER）和线粒体的重要桥梁。囊泡相关膜蛋白相关蛋白 B (VAPB) 和蛋白酪氨酸磷酸酶相互作用蛋白 51 (PTPIP51) 负责 MAM 的形成和稳定性，与多种疾病的发病机制有关。然而，MAM 在缺血性中风 (IS) 中的作用仍不清楚。我们的目的是研究MAMs束缚蛋白VAPB-PTPIP51在实验性脑缺血中的作用。方法我们通过使用小鼠大脑中动脉闭塞（MCAO）模型模拟脑缺血再灌注损伤（CIRI）。结果我们观察到VAPB-PTPIP51表达减少在脑组织中。我们的研究结果表明 MCAO 后 MAM 受损，通过透射电子显微镜 (TEM) 观察到线粒体-内质网接触 (MERC) 覆盖范围减少和距离增加。敲低 VAPB 或 PTPIP51 后，MAM 的损伤加剧，伴随着过度的自噬激活和活性氧 (ROS) 产生的增加，导致梗死面积扩大并加剧神经功能缺损。值得注意的是，我们观察到这种损伤与 PI3K/AKT/mTOR 通路的抑制相伴，并通过 PI3K 激活剂治疗成功减轻。结论我们的研究结果表明，IS 后 VAPB-PTPIP51 表达的下调介导了 MAM 的结构损伤。这可能通过抑制PI3K通路和激活自噬来加剧CIRI，从而为IS提供新的治疗靶点。

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Mitochondria‐associated endoplasmic reticulum membranes tethering protein VAPB‐PTPIP51 protects against ischemic stroke through inhibiting the activation of autophagy

AimsMitochondria‐associated endoplasmic reticulum membranes (MAMs) serve as a crucial bridge connecting the endoplasmic reticulum (ER) and mitochondria within cells. Vesicle‐associated membrane protein‐associated protein B (VAPB) and protein tyrosine phosphatase interacting protein 51 (PTPIP51) are responsible for the formation and stability of MAMs, which have been implicated in the pathogenesis of various diseases. However, the role of MAMs in ischemic stroke (IS) remains unclear. We aimed to investigate the role of MAMs tethering protein VAPB‐PTPIP51 in experimental cerebral ischemia.MethodsWe simulated cerebral ischemia–reperfusion injury (CIRI) by using a mouse middle cerebral artery occlusion (MCAO) model.ResultsWe observed a decrease in VAPB‐PTPIP51 expression in the brain tissue. Our findings suggested compromised MAMs after MCAO, as a decreased mitochondria–ER contact (MERC) coverage and an increased distance were observed through the transmission electron microscope (TEM). Upon VAPB or PTPIP51 knockdown, the damage to MAMs was exacerbated, accompanied by excessive autophagy activation and increased reactive oxygen species (ROS) production, resulting in an enlarged infarct area and exacerbated neurological deficits. Notably, we observed that this damage was concomitant with the inhibition of the PI3K/AKT/mTOR pathway and was successfully mitigated by the treatment with the PI3K activator.ConclusionsOur findings suggest that the downregulation of VAPB‐PTPIP51 expression after IS mediates structural damage to MAMs. This may exacerbate CIRI by inhibiting the PI3K pathway and activating autophagy, thus providing new therapeutic targets for IS.

更新日期：2024-04-08

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