The RNA-binding protein HuD promotes spinal GAP43 overexpression in antiretroviral-induced neuropathy
The RNA-binding protein HuD promotes spinal GAP43 overexpression in antiretroviral-induced neuropathy
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DOI：
10.1016/j.expneurol.2014.05.017
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发表时间：
2014-11
影响因子：
5.3
通讯作者：
M. D. Sanna;A. Quattrone;Tommaso Mello;C. Ghelardini;N. Galeotti
中科院分区：
文献类型：
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作者：
M. D. Sanna;A. Quattrone;Tommaso Mello;C. Ghelardini;N. Galeotti
已知核苷逆转录酶抑制剂 (NRTI) 会产生疼痛性神经病，并增强艾滋病患者因 HIV-1 感染而产生的疼痛过敏状态，导致抗逆转录病毒治疗中止，从而限制病毒抑制策略。 NRTI 导致神经性疼痛发生的机制尚不清楚。在当前的研究中，我们测试了这样的假设：HuD（一种 RNA 结合蛋白，已知是神经元分化和存活的重要促进剂）可能参与对 NRTI 诱导的神经病变的反应。小鼠腹腔内单次注射 2',3'-二脱氧胞苷 (ddC) 可诱导抗逆转录病毒神经病变。 HuD 在生理上在体细胞的细胞质以及 DRG 和脊髓内神经元的轴突中表达，并且在 ddC 处理后显着过度表达。 ddC 上调脊髓 GAP43 蛋白（神经再生的标志物），并且这种增加被 HuD 沉默所抵消。 GAP43 和 HuD 共定位于 DRG 和脊髓背角 (SDH) 轴突，施用抗 GAP43 抗体会加剧 ddC 诱导的轴突损伤。施用蛋白激酶 C (PKC) 抑制剂或 PKCγ 沉默可阻止 HuD 和 GAP43 表达增加。相反，用 PKC 激活剂 PDBu 治疗可增强 HuD 和 GAP43 过度表达，证明存在由 ddC 激活的脊髓 PKC 依赖性 HuD-GAP43 通路。这些结果表明，HuD 募集和 GAP43 蛋白增加是与抗逆转录病毒诱导的神经退行性过程的反应有关的机械相关事件。
Nucleoside reverse transcriptase inhibitors (NRTIs) are known to produce painful neuropathies and to enhance states of pain hypersensitivity produced by HIV-1 infection in patients with AIDS leading to discontinuation of antiretroviral therapy, thus limiting viral suppression strategies. The mechanisms by which NRTIs contribute to the development of neuropathic pain are not known. In the current study, we tested the hypothesis that HuD, an RNA binding protein known to be an essential promoter of neuronal differentiation and survival, might be involved in the response to NRTI-induced neuropathy. Antiretroviral neuropathy was induced by a single intraperitoneal administration of 2′,3′-dideoxycytidine (ddC) in mice. HuD was physiologically expressed in the cytoplasm of the soma and in axons of neurons within DRG and spinal cord and was considerably overexpressed following ddC treatment. ddC up-regulated spinal GAP43 protein, a marker of neuroregeneration, and this increase was counteracted by HuD silencing. GAP43 and HuD colocalize in DRG and spinal dorsal horn (SDH) axons and administration of an anti-GAP43 antibody aggravated the ddC-induced axonal damage. The administration of a protein kinase C (PKC) inhibitor or the PKCγ silencing prevented both HuD and GAP43 increased expression. Conversely, treatment with the PKC activator PDBu potentiated HuD and GAP43 overexpression, demonstrating the presence of a spinal PKC-dependent HuD–GAP43 pathway activated by ddC. These results indicated that HuD recruitment and GAP43 protein increase are mechanistically linked events involved in the response to antiretroviral-induced neurodegenerative processes.