More Insight into BDNF against Neurodegeneration: Anti-Apoptosis, Anti-Oxidation, and Suppression of Autophagy.
More Insight into BDNF against Neurodegeneration: Anti-Apoptosis, Anti-Oxidation, and Suppression of Autophagy.
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DOI：
10.3390/ijms18030545
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发表时间：
2017-03-03
影响因子：
5.6
通讯作者：
Yang DI
中科院分区：
文献类型：
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作者：
Chen SD;Wu CL;Hwang WC;Yang DI
脑源性神经营养因子（brain-derived neurotrophic factor，BDNF）除了具有神经营养作用外，还具有抗凋亡、抗氧化、抑制自噬等神经保护作用。我们已经表明，BDNF触发多种机制，赋予神经元抵抗3-硝基丙酸（3-NP）诱导的线粒体功能障碍，在原代大鼠皮层文化。BDNF的有益作用包括诱导抗氧化硫氧还蛋白，从而表达抗凋亡B细胞淋巴瘤2（Bcl-2）以及促红细胞生成素（EPO）依赖性刺激音刺猬（SHH）。我们进一步发现，BDNF可能带来的表达硫氧还蛋白，ATP依赖性的抗氧化酶，以抵消线粒体抑制皮层神经元。最近，我们对BDNF的另一种新的抗氧化机制提供了见解，其涉及增加sestrin 2的表达以赋予神经元对3-NP诱导的氧化应激的抗性; BDNF对sestrin 2的诱导需要激活涉及一氧化氮（NO）、环磷酸鸟苷（cGMP）依赖性蛋白激酶（PKG）和核因子-κB（NF-κB）的通路。除了抗细胞凋亡和抗氧化，我们在最近的研究中证明，BDNF可以激活哺乳动物雷帕霉素靶蛋白（mTOR），从而激活转录因子c-Jun，从而刺激p62/隔离体-1的表达，以抑制3-NP暴露导致的自噬增加。总之，我们的研究结果提供了深入了解BDNF对线粒体功能障碍的多方面保护机制，这些线粒体功能障碍通常与许多慢性神经退行性疾病的发病机制相关。对BDNF诱导的保护性信号通路的描述将为开发新的治疗方案以阻止或预防神经变性的进展提供理论基础。
In addition to its well-established neurotrophic action, brain-derived neurotrophic factor (BDNF) also possesses other neuroprotective effects including anti-apoptosis, anti-oxidation, and suppression of autophagy. We have shown before that BDNF triggers multiple mechanisms to confer neuronal resistance against 3-nitropropionic acid (3-NP)-induced mitochondrial dysfunction in primary rat cortical cultures. The beneficial effects of BDNF involve the induction of anti-oxidative thioredoxin with the resultant expression of anti-apoptotic B-cell lymphoma 2 (Bcl-2) as well as erythropoietin (EPO)-dependent stimulation of sonic hedgehog (SHH). We further revealed that BDNF may bring the expression of sulfiredoxin, an ATP-dependent antioxidant enzyme, to offset mitochondrial inhibition in cortical neurons. Recently, we provided insights into another novel anti-oxidative mechanism of BDNF, which involves the augmentation of sestrin2 expression to endow neuronal resistance against oxidative stress induced by 3-NP; BDNF induction of sestrin2 entails the activation of a pathway involving nitric oxide (NO), cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG), and nuclear factor-κB (NF-κB). Apart from anti-apoptosis and anti-oxidation, we demonstrated in our most recent study that BDNF may activate the mammalian target of rapamycin (mTOR) with resultant activation of transcription factor c-Jun, thereby stimulating the expression of p62/sequestosome-1 to suppress heightened autophagy as a result of 3-NP exposure. Together, our results provide in-depth insight into multi-faceted protective mechanisms of BDNF against mitochondrial dysfunction commonly associated with the pathogenesis of many chronic neurodegenerative disorders. Delineation of the protective signaling pathways elicited by BDNF would endow a rationale to develop novel therapeutic regimens to halt or prevent the progression of neurodegeneration.