PINCH-mediated CNS cell dysfunction and tauopathy in HIV

 描述(由申请人提供)：艾滋病毒+老年患者占艾滋病毒人群的很大比例，因为成功的抗逆转录病毒药物显著延长了寿命。然而，在艾滋病毒感染的情况下，年龄的增加会产生一系列独特的中枢神经系统并发症，包括与年龄相关的疾病的更快发病和进展、蛋白质质量控制的丧失以及异常蛋白质的积累。在HIV脑炎和阿尔茨海默氏症等神经退行性疾病中积累在大脑中的一种这样的蛋白质是过度磷酸化的Tau(HpTau)。HpTau的积累会导致神经元功能障碍，从而导致认知障碍。整合素连接蛋白激酶(ILK)、AKT、GSK3β等激酶的异常激活参与了Tau的磷酸化。同样，包括蛋白磷酸酶1-α(Pp1-α)和整合素连接的相关磷酸酶(ILKAP)在内的磷酸酶的失调也阻止了Tau的去磷酸化。尽管其机制尚不清楚，但已知HIV蛋白Tat可诱导hpTau的形成。Tat是在HIV感染期间在大脑中产生的，并进入神经元，在那里它改变了参与Tau磷酸化的激酶和磷酸酶的信号。在此背景下，我们发现了一种名为PINCH的蛋白质，它能与ILK、PP1DNA结合，并介导AKT和GSK3α的β活性。TAT增加了神经元中Pinch的表达，并扰乱了Pinch对激酶和磷酸酶的正常控制。此外，TAT直接与pp1α结合，并与ILKAP竞争细胞生存信号。我们的新研究表明，在HIV患者的大脑和脑脊液中，Pinch和hpTau显著增加，并相互结合。细胞培养和HIV的小鼠模型证实了这些发现。然而，如果我们在TAT存在的情况下阻止Pinch表达，则检测到的hpTau较少。这些数据使我们假设，在HIV感染中，TAT扰乱了Pinch通路的正常功能，导致hpTau增加和神经元功能障碍。我们提出了3个特定的目标，以在生化、行为和神经病理水平上验证我们的假设，这些水平与HIV患者群体的临床参数有关。这些研究的目标是将生化途径与我们在艾滋病毒患者群体中的发现联系起来。这些结果可能为研究艾滋病毒相关的肌萎缩侧索硬化症开辟新的方向，并将为年龄和疾病相关病理学的治疗干预提供机会。

 DESCRIPTION (provided by applicant): Aged HIV+ individuals represent a large proportion of the HIV population as lifespans are extended significantly by successful anti-retroviral medications. However, increased age in the presence of HIV infection creates a unique set of central nervous system complications that include more rapid onset and progression of age- related diseases, loss of protein quality control and accumulation of aberrant proteins. One such protein that accumulates in the brain in neurodegenerative diseases like HIV encephalitis and Alzheimer's is hyperphosphorylated Tau (hpTau). Accumulation of hpTau causes neuronal dysfunction that can lead to cognitive impairments. Aberrant activation of kinases such as integrin linked kinase (ILK), AKT, GSK3β and others contribute to the phosphorylation of Tau. Likewise, dysregulation of phosphatases including protein phosphatase 1-α (PP1α) and integrin linked associated phosphatase (ILKAP) prevent de-phosphorylation of Tau. Although the mechanisms for this are unclear, it is known that the HIV protein Tat induces hpTau formation. Tat is produced in the brain during HIV infection and enters into neurons where it alters signaling of the kinases and phosphatases involved in Tau phosphorylation. In this context, we have discovered a protein called PINCH that binds ILK, PP1α and mediates AKT and GSK3β kinases activities. Tat increases PINCH expression in neurons and disrupts PINCH's normal control of kinases and phosphatases. Moreover, Tat binds directly to PP1α and competes with ILKAP for cell survival signaling. Our new studies show that in HIV patients' brains and cerebrospinal fluid, PINCH and hpTau increase significantly and bind to one another. Cell culture and mouse models of HIV confirm these findings. However, if we block PINCH expression in the presence of Tat, less hpTau is detected. These data led us to hypothesize that in HIV infection, Tat disrupts the normal functions of the PINCH pathway leading to increased hpTau and neuronal dysfunction. We propose 3 Specific Aims to test our hypothesis at biochemical, behavioral, and neuropathological levels that link with clinical parameters in HIV patient populations. The goal of these studies is to link biochemical pathways to our findings in HIV patient populations. These results may open new directions to study HIV-associated tauopathy and will provide opportunities for therapeutic interventions in age- and disease-related pathologies.