Mechanisms of HIV-1 Tat neurotoxicity via CDK5 translocation and hyper-activation: role in HIV-associated neurocognitive disorders.
Mechanisms of HIV-1 Tat neurotoxicity via CDK5 translocation and hyper-activation: role in HIV-associated neurocognitive disorders.
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DOI：
10.2174/1570162x13666150311164201
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发表时间：
2015
影响因子：
1
通讯作者：
Masliah E
中科院分区：
文献类型：
--
作者：
Fields JA;Dumaop W;Crews L;Adame A;Spencer B;Metcalf J;He J;Rockenstein E;Masliah E
更有效的抗逆转录病毒疗法的出现降低了艾滋病毒痴呆的频率，然而，与艾滋病毒相关的轻度神经认知障碍（HAND）的患病率实际上正在上升。HAND的神经退行性机制可能包括由分泌的HIV-1蛋白（如Tat、gp120和Nef）引起的毒性，这些蛋白可以激活神经炎症途径，阻断自噬，促进兴奋毒性、氧化应激、线粒体功能障碍和信号通路失调。最近的研究表明，Tat可能干扰涉及细胞骨架调节、细胞存活和细胞周期再进入的几种信号转导机制。其中，Tat已被证明可超激活周期蛋白依赖性激酶[CDK] 5，该激酶是参与细胞迁移、血管生成、神经发生和突触可塑性的丝氨酸/苏氨酸CDKs的成员。CDK5通过与其调控亚基p35或p39结合而激活。在这篇论文中，我们回顾了证据表明Tat通过钙调节失调，促进p35到p25的calpain-1裂解，进而过度激活CDK5，导致下游靶点如Tau，塌陷蛋白反应介质蛋白-2 [CRMP2]，双皮质素[DCX]和MEF2的异常磷酸化。我们还提供了新的数据，表明Tat干扰CDK5在细胞核和细胞质之间的运输。这导致CDK5在细胞质中的长期存在，导致异常磷酸化的细胞质靶标的积累[例如：Tau， CRMP2, DCX]，损害神经元功能并最终导致细胞死亡。使用阻断Tat介导的CDK5超激活的化合物的新治疗方法可能在HAND的管理中具有价值。
The advent of more effective antiretroviral therapies has reduced the frequency of HIV dementia, however the prevalence of milder HIV associated neurocognitive disorders [HAND] is actually rising. Neurodegenerative mechanisms in HAND might include toxicity by secreted HIV-1 proteins such as Tat, gp120 and Nef that could activate neuro-inflammatory pathways, block autophagy, promote excitotoxicity, oxidative stress, mitochondrial dysfunction and dysregulation of signaling pathways. Recent studies have shown that Tat could interfere with several signal transduction mechanisms involved in cytoskeletal regulation, cell survival and cell cycle re-entry. Among them, Tat has been shown to hyper-activate cyclin-dependent kinase [CDK] 5, a member of the Ser/Thr CDKs involved in cell migration, angiogenesis, neurogenesis and synaptic plasticity. CDK5 is activated by binding to its regulatory subunit, p35 or p39. For this manuscript we review evidence showing that Tat, via calcium dysregulation, promotes calpain-1 cleavage of p35 to p25, which in turn hyper-activates CDK5 resulting in abnormal phosphorylation of downstream targets such as Tau, collapsin response mediator protein-2 [CRMP2], doublecortin [DCX] and MEF2. We also present new data showing that Tat interferes with the trafficking of CDK5 between the nucleus and cytoplasm. This results in prolonged presence of CDK5 in the cytoplasm leading to accumulation of aberrantly phosphorylated cytoplasmic targets [e.g.: Tau, CRMP2, DCX] that impair neuronal function and eventually lead to cell death. Novel therapeutic approaches with compounds that block Tat mediated hyper-activation of CDK5 might be of value in the management of HAND.
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影响因子：
15.1
作者：
Crews L;Ruf R;Patrick C;Dumaop W;Trejo-Morales M;Achim CL;Rockenstein E;Masliah E
通讯作者：
Masliah E
影响因子：
9.9
作者：
Brew, BJ;Pemberton, L;Hagberg, L
通讯作者：
Hagberg, L
影响因子：
3.7
作者：
Crews L;Spencer B;Desplats P;Patrick C;Paulino A;Rockenstein E;Hansen L;Adame A;Galasko D;Masliah E
通讯作者：
Masliah E
影响因子：
3.5
作者：
BAUMANN, K;MANDELKOW, EM;MANDELKOW, E
通讯作者：
MANDELKOW, E
影响因子：
8.8
作者：
Bharti, Ajay R.;Letendre, Scott L.;Grant, Igor
通讯作者：
Grant, Igor