HIV-1 Tat protein variants: critical role for the cysteine region in synaptodendritic injury.
HIV-1 Tat protein variants: critical role for the cysteine region in synaptodendritic injury.
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DOI：
10.1016/j.expneurol.2013.06.020
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发表时间：
2013-10
影响因子：
5.3
通讯作者：
Booze, Rosemarie M.
中科院分区：
文献类型：
--
作者：
Bertrand, Sarah J.;Aksenova, Marina V.;Mactutus, Charles F.;Booze, Rosemarie M.
HIV-1在感染早期就进入中枢神经系统；虽然HIV-1不直接感染神经元，但HIV-1可能引起多种神经系统疾病。 HIV-1 中已发现神经元损失，但突触树突损伤与 HIV-1 的神经认知障碍更为密切相关。 HIV-1 转录反式激活蛋白 (Tat) 会对神经元造成直接和间接损伤。 Tat 富含半胱氨酸的结构域（残基 22-37）对于产生神经元死亡非常重要；然而，人们对 Tat 蛋白功能域对树突网络的影响知之甚少。使用细胞检查 HIV-1 Tat 1-101 进化枝 B 和 C、Tat 1-86 和 Tat 1-72 蛋白以及新肽（截短的 47-57、1-72δ31-61 和 1-86，在 cys22 处突变）产生早期突触树突损伤（24 小时）相对于后期细胞死亡（48 小时）的能力。文化。用 Tat 蛋白 1-72、1-86 和 1-101B 处理原代海马神经元，导致 F-肌动蛋白标记的斑点早期显着减少，表明这些肽在突触树突损伤中发挥作用。具有突变、缺失或缺乏半胱氨酸丰富区域（1-86[Cys22]、1-101C、1-72δ31-61 或 47-57）的变体不会导致富含 F-肌动蛋白的斑点显着减少。 Tat 1-72、1-86 和 1-101B 蛋白彼此之间没有显着差异，表明第二个外显子（73-86 或 73-101）在 F-肌动蛋白斑点的减少中没有发挥显着作用。相反，具有突变、缺失或缺乏半胱氨酸丰富结构域 (22-37) 的肽未能产生 F-肌动蛋白点的丢失，表明富含半胱氨酸结构域在突触树突损伤中发挥关键作用。总的来说，这些结果表明，对于 Tat 蛋白，1) 突触树突损伤发生得较早，相对于细胞死亡，2) 第一个外显子富含半胱氨酸的结构域是突触损失的关键。预防这种早期突触丧失可能会减轻 HIV-1 相关的神经认知障碍。
HIV-1 enters the central nervous system early in infection; although HIV-1 does not directly infect neurons, HIV-1 may cause a variety of neurological disorders. Neuronal loss has been found in HIV-1, but synaptodendritic injury is more closely associated with the neurocognitive disorders of HIV-1. The HIV-1 transactivator of transcription (Tat) protein causes direct and indirect damage to neurons. The cysteine rich domain (residues 22–37) of Tat is important for producing neuronal death; however, little is known about the effects of the Tat protein functional domains on the dendritic network. The ability of HIV-1 Tat 1–101 clades B and C, Tat 1–86 and Tat 1–72 proteins, as well as novel peptides (truncated 47–57, 1–72δ31–61, and 1–86 with a mutation at cys22) to produce early synaptodendritic injury (24 hrs), relative to later cell death (48 hrs), was examined using cell culture. Treatment of primary hippocampal neurons with Tat proteins 1–72, 1–86 and 1–101B produced a significant early reduction in F-actin labeled puncta, implicating that these peptides play a role in synaptodendritic injury. Variants with a mutation, deletion, or lack of a cysteine rich region (1–86[Cys22], 1–101C, 1–72δ31–61, or 47–57), did not cause a significant reduction in F-actin rich puncta. Tat 1–72, 1–86, and 1–101B proteins did not significantly differ from one another, indicating the second exon (73–86 or 73–101) does not play a significant role in the reduction of F-actin puncta. Conversely, peptides with a mutation, deletion, or lack of the cysteine rich domain (22–37) failed to produce a loss of F-actin puncta, indicating that the cysteine rich domain plays a key role in synaptodendritic injury. Collectively, these results suggest that for Tat proteins, 1) synaptodendritic injury occurs early, relative to cell death, and 2) the cysteine rich domain of the first exon is key for synaptic loss. Preventing such early synaptic loss may attenuate HIV-1 associated neurocognitive disorders.
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影响因子：
2.9
作者：
Fitting, Sylvia;Booze, Rosemarie M.;Mactutus, Charles F.
通讯作者：
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2.5
作者：
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Booze, RM