Human immunodeficiency virus type 1 alters brain-derived neurotrophic factor processing in neurons.
Human immunodeficiency virus type 1 alters brain-derived neurotrophic factor processing in neurons.
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DOI：
10.1523/jneurosci.0865-12.2012
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发表时间：
2012-07-11
期刊：
影响因子：
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通讯作者：
Mocchetti I
中科院分区：
文献类型：
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作者：
Bachis A;Avdoshina V;Zecca L;Parsadanian M;Mocchetti I
导致人类免疫缺陷病毒1型（HIV）阳性受试者突触简化和神经元凋亡的分子机制尚不清楚。HIV蛋白gp 120减少了神经元突起的长度，类似于proneurotrophin pro brain-derived neurotrophic factor（proBDNF）。有趣的是，proBDNF和gp 120的作用都被p75神经营养因子受体的抑制剂阻断，这表明proBDNF和gp 120具有相似的神经毒性机制。因此，我们测试了gp 120影响proBDNF释放的假设。使用大鼠原代神经元，我们观察到，gp 120促进了时间依赖性的细胞内和细胞外积累的proBDNF伴随着减少成熟的BDNF。在认知和运动障碍的HIV阳性受试者的死后大脑中证实了proBDNF/成熟BDNF比例的类似失衡。因此，可以想象，制定的假设，艾滋病毒的神经毒性包括gp 120介导的BDNF加工的改变。为了确定gp 120产生proBDNF积累的细胞机制，我们分别检测了蛋白水解切割proBDNF、弗林蛋白酶和组织纤溶酶原的细胞内和细胞外酶的水平。在暴露于gp 120的大鼠神经元中，细胞死亡前细胞内弗林蛋白酶水平下降，而组织纤溶酶原仅在凋亡过程中发生变化。我们的数据表明，艾滋病毒，通过gp 120，减少proBDNF的处理，通过影响弗林蛋白酶水平，因此导致抗凋亡和促凋亡神经营养因子之间的平衡改变。我们的研究确定了一种新的机制，可以解释艾滋病毒如何促进神经元损伤。
The molecular mechanisms leading to synaptic simplification and neuronal apoptosis in human immunodeficiency virus type 1 (HIV) positive subjects are unknown. The HIV protein gp120 reduced the length of neuronal processes similarly to the proneurotrophin pro brain-derived neurotrophic factor (proBDNF). Intriguingly, the effects of both proBDNF and gp120 were blocked by inhibitors of the p75 neurotrophin receptor, suggesting that proBDNF and gp120 share a similar mechanism of neurotoxicity. Therefore, we tested the hypothesis that gp120 affects the release of proBDNF. Using rat primary neurons we observed that gp120 promotes a time-dependent intracellular and extracellular accumulation of proBDNF concomitantly with a decrease in mature BDNF. A similar imbalance in the ratio proBDNF/mature BDNF was confirmed in postmortem brains of HIV positive subjects cognitive and motor impaired. Therefore, it is conceivable to formulate the hypothesis that HIV neurotoxicity includes a gp120-mediated alteration of BDNF processing. To determine the cellular mechanism whereby gp120 produces an accumulation of proBDNF, we examined the levels of intracellular and extracellular enzymes that proteolytically cleave proBDNF, furin and tissue plasminogen, respectively. In rat neurons exposed to gp120, intracellular furin levels decreased prior to cell death whereas tissue plasminogen changed only during apoptosis. Our data suggest that HIV, through gp120, reduces proBDNF processing by affecting furin levels and therefore causes an altered balance between anti-apoptotic and pro-apoptotic neurotrophins. Our studies identify a new mechanism that may explain how HIV promotes neuronal injury.