Targeting Mitochondrial Superoxide in Angelman Syndrome

描述（由申请人提供）：Angelman综合征（AS）是一种人类神经系统疾病，其相关症状包括认知障碍、运动异常和癫痫。在大多数情况下，AS是由15号染色体上的小部分缺失引起的，其中包括UBE3A基因。UBE3A基因编码一种称为泛素连接酶E3A（也称为E6-AP）的酶，该酶是一种将多泛素链共价连接到蛋白质上的酶家族中的一员，该酶通过26S蛋白酶体识别和降解蛋白质。已经建立了一个AS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，这些与人类观察到的神经系统改变相关。海马依赖的学习和记忆在AS模型小鼠中受损，长期增强（LTP）也受损，LTP是一种长期形式的突触可塑性，被认为是记忆的细胞基质。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氧化应激的主要来源之一，我们最近已经表明，减少线粒体来源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损伤。综上所述，这些发现使我们假设线粒体来源的超氧化物有助于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，线粒体超氧化物水平在AS小鼠海马中升高。在此，我们建议通过药理学和遗传学方法确定降低线粒体来源的超氧化物水平是否可以1)拯救AS小鼠海马LTP缺陷，2)逆转AS小鼠的记忆障碍，以及3)改善AS小鼠的运动表现和减少听原性癫痫发作。这些研究的结果将有助于深入了解氧化应激是否与AS相关，它如何影响海马突触可塑性，海马依赖记忆和AS中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能成为治疗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. PUBLIC HEALTH RELEVANCE: A mouse model of Angelman syndrome (AS) has been generated that exhibits symptoms consistent with the human genetic disorder, including cognitive impairment, motor abnormalities, and epilepsy. We have proposed to determine whether reducing oxidative stress caused by mitochondrial dysfunction can reverse the aforementioned neurological abnormalities in AS model mice. These studies will determine whether reducing mitochondrial-derived oxidative stress is a potential therapy for the treatment of individuals with AS.