HIV Glycoprotein Gp120 Impairs Fast Axonal Transport by Activating Tak1 Signaling Pathways.
HIV Glycoprotein Gp120 Impairs Fast Axonal Transport by Activating Tak1 Signaling Pathways.
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DOI：
10.1177/1759091416679073
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发表时间：
2016-12
期刊：
影响因子：
4.7
通讯作者：
Brady ST
中科院分区：
文献类型：
--
作者：
Berth SH;Mesnard-Hoaglin N;Wang B;Kim H;Song Y;Sapar M;Morfini G;Brady ST
感觉神经病变是HIV最常见的神经系统并发症。其中，远端感觉性多发性神经病（DSP）是由HIV感染直接引起的，其特征在于背根神经节（DRG）神经元的长度依赖性轴突变性。DSP轴突变性的机制尚不清楚，但最近的实验表明，HIV糖蛋白gp 120是内化和定位在DRG神经元的轴突内。基于这些发现，我们研究了轴突内gp 120是否可能损害快速轴突运输（FAT），这是一个对轴突隔室的适当维护至关重要的细胞过程。值得注意的是，我们发现gp 120严重损害了顺行和逆行脂肪。药理学实验为这些作用提供了机制基础，揭示了各种磷酸转移酶参与这种毒性作用，包括促分裂原活化蛋白激酶途径（Tak-1、p38和c-Jun N-末端激酶（JNK））的成员、κ-B-激酶2（IKK 2）抑制剂和PP 1。在细胞系和原代培养物中的生化实验和轴突生长测定扩展了这些发现。使用Tak-1抑制剂拯救了由gp 120引起的DRG神经元轴突生长障碍，这表明Tak-1丝裂原活化蛋白激酶通路与gp 120神经毒性有关。综上所述，这些观察结果表明，在FAT中基于激酶的损伤代表了一种新的机制，其潜在的gp 120神经毒性与在DSP中观察到的退变一致。用特异性激酶抑制剂靶向FAT中基于gp 120的损伤可能提供一种新的治疗策略来预防DSP中的轴突变性。
Sensory neuropathies are the most common neurological complication of HIV. Of these, distal sensory polyneuropathy (DSP) is directly caused by HIV infection and characterized by length-dependent axonal degeneration of dorsal root ganglion (DRG) neurons. Mechanisms for axonal degeneration in DSP remain unclear, but recent experiments revealed that the HIV glycoprotein gp120 is internalized and localized within axons of DRG neurons. Based on these findings, we investigated whether intra-axonal gp120 might impair fast axonal transport (FAT), a cellular process critical for appropriate maintenance of the axonal compartment. Significantly, we found that gp120 severely impaired both anterograde and retrograde FAT. Providing a mechanistic basis for these effects, pharmacological experiments revealed an involvement of various phosphotransferases in this toxic effect, including members of mitogen-activated protein kinase pathways (Tak-1, p38, and c-Jun N-terminal Kinase (JNK)), inhibitor of kappa-B-kinase 2 (IKK2), and PP1. Biochemical experiments and axonal outgrowth assays in cell lines and primary cultures extended these findings. Impairments in neurite outgrowth in DRG neurons by gp120 were rescued using a Tak-1 inhibitor, implicating a Tak-1 mitogen-activated protein kinase pathway in gp120 neurotoxicity. Taken together, these observations indicate that kinase-based impairments in FAT represent a novel mechanism underlying gp120 neurotoxicity consistent with the dying-back degeneration seen in DSP. Targeting gp120-based impairments in FAT with specific kinase inhibitors might provide a novel therapeutic strategy to prevent axonal degeneration in DSP.
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影响因子：
4.7
作者：
Ghil, SH;Kim, BJ;Suh-Kim, H
通讯作者：
Suh-Kim, H
影响因子：
2.2
作者：
Dorsey, Susan G.;Morton, Patricia Gonce
通讯作者：
Morton, Patricia Gonce
影响因子：
25
作者：
Bosco, Daryl A.;Morfini, Gerardo;Karabacak, N. Murat;Song, Yuyu;Gros-Louis, Francois;Pasinelli, Piera;Goolsby, Holly;Fontaine, Benjamin A.;Lemay, Nathan;McKenna-Yasek, Diane;Frosch, Matthew P.;Agar, Jeffrey N.;Julien, Jean-Pierre;Brady, Scott T.;Brown, Robert H., Jr.
通讯作者：
Brown, Robert H., Jr.
影响因子：
9.2
作者：
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通讯作者：
Horuk, R
影响因子：
3.5
作者：
Ebbing, Bettina;Mann, Klaudiusz;Woehlke, Guenther
通讯作者：
Woehlke, Guenther