Zinc induces motor neuron death via a selective inhibition of brain-derived neurotrophic factor activity
Zinc induces motor neuron death via a selective inhibition of brain-derived neurotrophic factor activity
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DOI：
10.1080/17482960801934015
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发表时间：
2008-01-01
影响因子：
--
通讯作者：
Ross, Gregory Michiel
中科院分区：
文献类型：
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作者：
Post, Joan Isabel;Eibl, Joseph Karl;Ross, Gregory Michiel
肌萎缩侧索硬化症是一种使人衰弱的疾病，由运动神经元退化和丧失引起。 Zn(2+) 在体外和体内的神经毒性潜力已得到充分证实；然而，锌的毒性机制仍不清楚。我们的实验室已证明 Zn(2+) 介导的神经营养素抑制可诱导细胞死亡。本研究通过评估锌在改变神经营养蛋白 BDNF（而非神经细胞因子 CNTF）方面对运动神经元存活的选择性，研究了这种金属离子的神经毒性机制。胚胎第15天大鼠脊髓运动神经元培养物维持在BDNF或CNTF中。末端脱氧核苷酸转移酶介导的 dUTP-地高辛缺口末端标记 (TUNEL) 染色显示，暴露于 100 μM Zn(2+) 显着增加了用 BDNF 维持的培养物中促凋亡神经元的数量，而这些条件对用 CNTF 维持的培养物没有影响。我们还证明了 BDNF 原体交联效率和 TrkB 受体与 BDNF 的交联受到 Zn(2+) 的显着抑制，表明 Zn(2+) 诱导的 BDNF 构象变化抑制了受体结合活性。这项研究揭示了一种机制，锌毒性是通过神经营养蛋白活性的选择性丧失而介导的，从而导致运动神经元死亡。
Amyotrophic lateral sclerosis is a debilitating disease that results from the deterioration and loss of motor neurons. The neurotoxic potential of Zn(2+), both in vitro and in vivo, has been well established; however, the mechanism(s) of zinc's toxicity remain unclear. Our laboratory has demonstrated that Zn(2+)-mediated inhibition of neurotrophins can induce cell death. The present study investigates the neurotoxic mechanism(s) of this metal ion by assessing zinc's selectivity in altering the neurotrophin BDNF, but not the neural cytokine CNTF, with respect to motor neuron survival. Embryonic day 15 rat spinal motor neuron cultures were maintained in either BDNF or CNTF. Terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling (TUNEL) staining showed that exposure to 100 mu M Zn(2+) significantly increased the number of pro-apoptotic neurons in cultures maintained with BDNF, while these conditions had no effect on cultures maintained with CNTF. We also demonstrate that BDNF protomer cross-linking efficiency and TrkB receptor cross-linking to BDNF are significantly inhibited by Zn(2+), suggesting that a Zn(2+)-induced change in BDNF conformation inhibits receptor-binding activity. This study reveals a mechanism by which zinc toxicity is mediated via a selective loss in neurotrophin activity resulting in motor neuron death.