The Synaptic Protein Economy in HIV/AID

描述（由申请人提供）：艾滋病毒/艾滋病患者可以活到更大的年龄，但我们仍然不知道艾滋病毒相关的神经认知障碍（HAND）是否或如何在衰老的大脑中加剧。我们将评估脑炎症通过改变泛素蛋白酶体系统（UPS）驱动HAND和脑老化之间相互作用的假设。UPS是神经元蛋白质周转的主要途径;它是突触增强、学习和记忆形成中正常的每分钟生理变化所必需的。UPS在防止脑老化过程中病理性神经退行性变中错误折叠的神经元蛋白的积累中起关键作用。我们证实了HAND患者大脑皮层的UPS异常：免疫蛋白酶体（IPS）对干扰素的反应是诱导的。IPS诱导与HIV相关的神经认知障碍（HAND）密切相关。这在病理学上是相关的，因为它在HIV脑炎（HIVE）和/或大脑中复制HIV浓度的受试者中普遍存在。它在解剖学上广泛存在于关键的神经元隔室中，包括突触、轴突和神经元核、胞体和孤立的突触体。该提案将测试IPS诱导通过病理性地转移UPS底物库来扰乱突触蛋白经济的假设，这改变了HAND和脑老化中的底物库、突触蛋白周转率和突触可塑性。第一个目标将使用人脑样本来确定IPS诱导如何影响UPS的大分子组装和酶功能，包括与突触蛋白的动态相互作用。第二个目标将使用干扰素刺激的混合脑细胞培养物来确定IPS诱导如何影响突触蛋白质周转和全酶动力学，并将确定抑制IPS是否逆转突触蛋白质经济中的这些变化。最终的目标将使用尸检标本来确定病理性脑老化期间错误折叠蛋白质的发病年龄或积累速率是否与IPS诱导相关。该计划总体上解决了HAND中突触功能障碍的一种非常新颖的机制，并对病理性脑老化和HIV/AIDS之间的相互作用机制具有重要意义。

DESCRIPTION (provided by applicant): People with HIV/AIDS survive to older ages, but we still do not know if or how HIV-associated neurocognitive disorders (HAND) is exacerbated in the aging brain. We will evaluate the hypotheses that brain inflammation drives an interaction between HAND and brain aging by modifying the ubiquitin proteasome system (UPS). The UPS is the main route of neuronal protein turnover; it is required for normal minute-to-minute physiological changes in synaptic potentiation, learning and memory formation. The UPS plays a key role in preventing the accumulation of misfolded neuronal proteins in pathological neurodegeneration during brain aging. We established that the UPS is abnormal in brain cortex of people with HAND: Immunoproteasomes (IPS) are induced in response to interferons. IPS induction was linked solidly with HIV-associated neurocognitive disorders (HAND). It was relevant pathologically because it was prevalent in subjects with HIV encephalitis (HIVE) and/or replicating HIV concentration in the brain. It was anatomically pervasive in critical neuronal compartments including synapses, axons and neuronal nuclei, perikarya, and isolated synaptosomes. The proposal will test the hypothesis that IPS induction perturbs the synaptic protein economy by diverting the UPS substrate repertoire pathologically, which alters the substrate repertoire, synaptic protein turnover, and synaptic plasticity in HAND and brain aging. The first aim will use human brain specimens to determine how IPS induction affects macromolecular assembly and enzymatic functions of the UPS, including the dynamic interaction with synaptic proteins. The second aim will use interferon-stimulated mixed brain cell cultures to determine how IPS induction influences synaptic protein turnover and holoenzyme kinetics, and will determine whether inhibiting the IPS reverses these changes in the synaptic protein economy. A final aim will use autopsy specimens to determine if the age-of-onset or rate-of-accumulation of misfolded proteins during pathological brain aging is perturbed in association with IPS induction. The program overall addresses a highly novel mechanism for synaptic dysfunction in HAND and has important implications for the mechanism of interaction between pathological brain aging and HIV/AIDS.