Targeting Mitochondrial Superoxide in Angelman Syndrome

描述(申请人提供)：Angelman综合征(AS)是一种人类神经疾病，与包括认知障碍、运动异常和癫痫在内的症状有关。在大多数情况下，AS是由15号染色体上包括UBE3A基因的一小部分缺失引起的。UBE3A基因编码一种名为泛素连接酶E3A(也称为E6-AP)的酶，它是将多聚泛素链共价连接到蛋白质上的一种酶，以信号传递26S蛋白酶体识别和降解它们的信号。已经建立了一种AS的小鼠模型，这些小鼠表现出癫痫发作、运动功能受损和认知缺陷，这些都与在人类观察到的神经变化有关。在AS模型鼠中，海马区依赖的学习和记忆受到损害，长时程增强(LTP)也是如此，LTP是一种长期存在的突触可塑性形式，被认为是记忆的细胞底物。最近有报道称，AS模型小鼠出现线粒体功能障碍。此外，线粒体被认为是细胞内氧化应激的主要来源之一，我们最近的研究表明，减少线粒体衍生的超氧化物可以挽救阿尔茨海默病模型小鼠的突触可塑性和记忆障碍。综上所述，这些发现使我们假设线粒体衍生的超氧化物有助于AS模型小鼠的突触可塑性和记忆障碍。与这一观点一致，我们的初步数据表明，AS小鼠海马区线粒体超氧化物水平升高。在这里，我们建议确定通过药理学和遗传学方法降低线粒体衍生的超氧化物歧化酶水平是否可以1)挽救AS小鼠表现出的海马LTP缺陷，2)逆转AS小鼠表现出的记忆损伤，3)改善AS小鼠表现出的运动能力和减少AS小鼠表现出的听源性癫痫发作。这些研究的结果应该有助于深入了解氧化应激是否与AS有关，它如何影响AS患者的海马区突触可塑性、海马区依赖记忆和其他形式的神经功能障碍，以及使用线粒体靶向抗氧化剂是否可以成为治疗AS患者的可行疗法。

DESCRIPTION (provided by applicant): Angelman syndrome (AS) is a human neurological disorder that is associated with symptoms that include cognitive impairment, motor abnormalities, and epilepsy. In most cases, AS is caused by the deletion of small portions on chromosome 15, which includes the UBE3A gene. The UBE3A gene encodes an enzyme termed ubiquitin ligase E3A (also termed E6-AP), which is one of a family of enzymes that covalently attaches polyubiquitin chains to proteins to signal for their recognition and degradation by the 26S proteasome. A mouse model of AS has been generated and these mice exhibit seizures, impaired motor function, and cognitive deficits that correlate with neurological alterations observed in humans. Hippocampus-dependent learning and memory is impaired in AS model mice, as is long-term potentiation (LTP), a long-lasting form of synaptic plasticity thought to be a cellular substrate for memory. Recently it was reported that AS model mice exhibit mitochondrial dysfunction. Moreover, mitochondria are considered to be one of the primary sources of oxidative stress in cells, and we recently have shown that reduction mitochondrial-derived superoxide can rescue synaptic plasticity and memory impairments in Alzheimer's disease model mice. Taken together, these findings have led us to hypothesize that mitochondrial-derived superoxide contributes to synaptic plasticity and memory impairments in AS model mice. Consistent with this idea, our preliminary data indicate that the levels of mitochondrial superoxide are elevated in the hippocampus of AS mice. Herein, we propose to determine whether reducing levels of mitochondrial-derived superoxide using pharmacological and genetic approaches can 1) rescue hippocampal LTP deficits displayed by AS mice, 2) reverse memory impairments displayed by AS mice, and 3) improve motor performance and reduce audiogenic seizures displayed by AS mice. The results of these studies should provide insight into whether oxidative stress is associated with AS, how it impacts hippocampal synaptic plasticity, hippocampus-dependent memory, and other forms of neurological dysfunction in AS, and whether use of mitochondria-targeted antioxidants could be a viable therapy for treating individuals with AS.