Role of Cathepsin D in U18666A-induced Neuronal Cell Death POTENTIAL IMPLICATION IN NIEMANN-PICK TYPE C DISEASE PATHOGENESIS
Role of Cathepsin D in U18666A-induced Neuronal Cell Death POTENTIAL IMPLICATION IN NIEMANN-PICK TYPE C DISEASE PATHOGENESIS
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DOI：
10.1074/jbc.m112.412460
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发表时间：
2013-02-01
影响因子：
4.8
通讯作者：
Kar, Satyabrata
中科院分区：
文献类型：
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作者：
Amritraj, Asha;Wang, Yanlin;Kar, Satyabrata
组织蛋白酶D是一种乙酰基蛋白酶，其在正常细胞功能和多种神经退行性疾病中起关键作用，包括C型尼曼-匹克（NPC）病，其特征在于胆固醇和鞘糖脂在许多组织（包括脑）中的细胞内积累。有证据表明，组织蛋白酶D的水平和活性显着增加，在NPC病理脆弱的神经元，但其参与神经变性仍不清楚。在本研究中，使用小鼠海马培养的神经元，我们评估了组织蛋白酶D的毒性诱导的U18666 A，II类两亲物，通过损害胆固醇的贩运，引发细胞死亡的意义，观察在NPC病理。我们的研究结果表明，U18666 A介导的毒性伴随着组织蛋白酶D mRNA和酶活性的增加，但总肽含量的减少。另一方面，在U18666 A处理的神经元中，组织蛋白酶D的胞质水平与细胞色素c和活化的半胱天冬酶3一起沿着增加。组织蛋白酶D抑制剂胃酶抑素A通过减弱这些信号机制部分保护神经元免受毒性。此外，下调组织蛋白酶D水平防止，而过度表达的蛋白酶增加，培养的N2 a细胞U18666 A诱导的毒性的脆弱性。我们还表明，细胞外组织蛋白酶D从U18666 A处理的神经元或应用外源性酶可以通过激活自噬途径诱导神经毒性。这些结果表明，增加的组织蛋白酶D的释放/激活可以触发神经退行性变和可能的NPC病理学的发展。因此，靶向组织蛋白酶D水平/活性可能为治疗NPC病理提供新的治疗机会。
Cathepsin D is an aspartyl protease that plays a crucial role in normal cellular functions and in a variety of neurodegenerative disorders, including Niemann-Pick type C (NPC) disease, which is characterized by intracellular accumulation of cholesterol and glycosphingolipids in many tissues, including the brain. There is evidence that the level and activity of cathepsin D increased markedly in vulnerable neurons in NPC pathology, but its involvement in neurodegeneration remains unclear. In the present study, using mouse hippocampal cultured neurons, we evaluated the significance of cathepsin D in toxicity induced by U18666A, a class II amphiphile, which triggers cell death by impairing the trafficking of cholesterol, as observed in NPC pathology. Our results showed that U18666A-mediated toxicity is accompanied by an increase in cathepsin D mRNA and enzyme activity but a decrease in the total peptide content. The cytosolic level of cathepsin D, on the other hand, was increased along with cytochrome c and activated caspase-3 in U18666A-treated neurons. The cathepsin D inhibitor, pepstatin A, partially protected neurons against toxicity by attenuating these signaling mechanisms. Additionally, down-regulation of cathepsin D level prevented, whereas overexpression of the protease increased, vulnerability of cultured N2a cells to U18666A-induced toxicity. We also showed that extracellular cathepsin D from U18666A-treated neurons or application of exogenous enzyme can induce neurotoxicity by activating the autophagic pathway. These results suggest that increased release/activation of cathepsin D can trigger neurodegeneration and possibly development of NPC pathology. Thus, targeting cathepsin D level/activity may provide a new therapeutic opportunity for the treatment of NPC pathology.