The Synaptic Protein Economy in HIV/AID

描述（由申请人提供）：艾滋病毒/艾滋病患者寿命更长，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。我们将通过修改泛素蛋白酶体系统（UPS）来评估脑炎症驱动HAND和脑衰老之间相互作用的假设。UPS是神经元蛋白转换的主要途径；它是突触增强、学习和记忆形成中每分钟的正常生理变化所必需的。UPS在防止脑衰老过程中病理性神经变性中错误折叠神经元蛋白的积累中起关键作用。我们发现HAND患者的大脑皮层UPS异常：免疫蛋白酶体（IPS）在干扰素的作用下被诱导。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。它在解剖学上普遍存在于关键的神经元室室，包括突触、轴突和神经元核、核周和分离的突触体。该提案将验证IPS诱导通过病理转移UPS底物库来扰乱突触蛋白经济的假设，这改变了底物库、突触蛋白周转和HAND和脑衰老中的突触可塑性。第一个目标将使用人脑标本来确定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来确定IPS诱导如何影响突触蛋白转换和全酶动力学，并将确定抑制IPS是否会逆转突触蛋白经济中的这些变化。最终目的是使用尸检标本来确定病理性脑衰老过程中错误折叠蛋白的发病年龄或积累速度是否与IPS诱导有关。该计划总体上解决了HAND突触功能障碍的一个高度新颖的机制，并对病理性脑老化与艾滋病毒/艾滋病之间相互作用的机制具有重要意义。

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. PUBLIC HEALTH RELEVANCE: "The project is important because it will clearly define a novel basic mechanism regarding how HIV infection in the brain disturbs learning and memory, and how HIV worsens brain degeneration during aging. The studies will determine if changes in brain proteins that occur can be blocked, in order to stop dementia and brain aging in HIV infected people"