Tubulin-mediated binding of human immunodeficiency virus-1 Tat to the cytoskeleton causes proteasomal-dependent degradation of microtubule-associated protein 2 and neuronal damage
Tubulin-mediated binding of human immunodeficiency virus-1 Tat to the cytoskeleton causes proteasomal-dependent degradation of microtubule-associated protein 2 and neuronal damage
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DOI：
10.1523/jneurosci.0603-06.2006
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发表时间：
2006-04-12
影响因子：
5.3
通讯作者：
Peruzzi, F
中科院分区：
文献类型：
--
作者：
Aprea, S;Del Valle, L;Peruzzi, F
CNS中人类免疫缺陷病毒（HIV）-1相关病理学的标志之一是神经元过程的恶化。尽管有越来越多的证据表明HIV-1反式激活因子达特诱导神经元毒性和细胞死亡，但与其对神经元细胞的有害作用直接相关的分子事件仍不清楚。在这项研究中，我们使用大鼠胚胎皮层神经元，并证明，达特导致微管相关蛋白2（MAP 2）的快速降解和细胞骨架丝的崩溃。达特作用于MAP 2稳定性的机制涉及塔特介导的蛋白酶体易位到微管细丝的位点。HIV脑病患者临床样本的免疫组织化学分析进一步显示，在小胶质细胞结节附近的皮质神经元中，MAP 2显著减少，细胞质20 S占优势。这些发现表明了达特对神经细胞作用的新机制。它涉及蛋白酶体介导的MAP 2降解，并可能导致MAP 2的丢失和在患有神经功能障碍的AIDS患者的脑中观察到的神经元损伤。
One of the hallmarks of human immunodeficiency virus (HIV)-1 associated pathology in the CNS is deterioration of neuronal processes. Although there is mounting evidence of neuronal toxicity and cell death induced by the HIV-1 transactivating factor Tat, the molecular events linked directly to its detrimental effect on neuronal cells remain unclear. In this study, we used rat embryonic cortical neurons and demonstrated that Tat causes rapid degradation of microtubule-associated protein 2 (MAP2) and the collapse of cytoskeletal filaments. The mechanism of Tat action on MAP2 stability involved Tat-mediated translocation of the proteasome to the site of microtubule filaments. Immunohistochemical analysis of clinical samples from patients with HIV encephalopathy further revealed a significant decrease in MAP2 with predominant cytoplasmic 20S in cortical neurons near microglial nodules. These findings indicate a novel mechanism for the action of Tat on neuronal cells. It involves proteasome-mediated MAP2 degradation and may account for the loss of MAP2 and neuronal damage observed in the brain of AIDS patients with neurological dysfunctions.