PINCH-mediated CNS cell dysfunction and tauopathy in HIV

 描述（由申请人提供）：老年艾滋病毒阳性个体占艾滋病毒感染者的很大比例，因为成功的抗逆转录病毒药物显著延长了寿命。然而，在HIV感染的情况下年龄的增加产生了一组独特的中枢神经系统并发症，包括年龄相关疾病的更快发作和进展、蛋白质质量控制的丧失和异常蛋白质的积累。在神经退行性疾病如HIV脑炎和阿尔茨海默氏症中在大脑中积累的一种这样的蛋白质是过度磷酸化的Tau（hpTau）。hpTau的积累引起神经元功能障碍，其可导致认知障碍。激酶如整联蛋白连接激酶（ILK）、AKT、GSK 3 β等的异常激活有助于Tau的磷酸化。同样，磷酸酶包括蛋白磷酸酶1-α（PP 1 α）和整合素连接相关磷酸酶（ILKAP）的失调阻止Tau的去磷酸化。尽管其机制尚不清楚，但已知HIV蛋白达特诱导hpTau形成。达特在HIV感染期间在大脑中产生，并进入神经元，在那里它改变Tau磷酸化中涉及的激酶和磷酸酶的信号传导。在此背景下，我们发现了一种名为PINCH的蛋白质，其结合ILK，PP 1 α并介导AKT和GSK 3 β激酶活性。达特增加神经元中的PINCH表达并破坏PINCH对激酶和磷酸酶的正常控制。此外，达特直接与PP 1 α结合，并与ILKAP竞争细胞存活信号。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小鼠模型证实了这些发现。然而，如果我们在达特存在下阻断PINCH表达，则检测到较少的hpTau。这些数据使我们假设在HIV感染中，达特破坏PINCH途径的正常功能，导致hpTau增加和神经元功能障碍。我们提出了3个具体目标，以检验我们的假设在生化，行为和神经病理水平，与临床参数在艾滋病毒患者人群。这些研究的目标是将生化途径与我们在HIV患者人群中的发现联系起来。这些结果可能为研究HIV相关的tau蛋白病开辟新的方向，并为年龄和疾病相关的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.