Targeting Mitochondrial Superoxide in Angelman Syndrome

描述（由申请人提供）：Angelman综合征（AS）是一种与认知障碍、运动异常和癫痫等症状相关的人类神经系统疾病。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UBE 3A基因。UBE 3A基因编码一种称为泛素连接酶E3 A（也称为E6-AP）的酶，其是将多聚泛素链共价连接至蛋白质以发出其被26 S蛋白酶体识别和降解的信号的酶家族之一。已经产生了AS的小鼠模型，并且这些小鼠表现出与在人类中观察到的神经改变相关的癫痫发作、运动功能受损和认知缺陷。海马依赖性学习和记忆在AS模型小鼠中受损，长时程增强（LTP）也是如此，长时程增强是突触可塑性的一种持久形式，被认为是记忆的细胞基质。近年来研究发现AS模型小鼠存在线粒体功能障碍。此外，线粒体被认为是细胞中氧化应激的主要来源之一，并且我们最近已经表明，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，脑源性超氧化物有助于突触可塑性和记忆障碍的AS模型小鼠。与这一想法相一致，我们的初步数据表明，线粒体超氧化物水平升高，在海马的AS小鼠。在此，我们建议使用药理学和遗传学方法来确定降低脑源性超氧化物的水平是否可以1）挽救AS小鼠显示的海马LTP缺陷，2）逆转AS小鼠显示的记忆障碍，以及3）改善运动表现并减少AS小鼠显示的听源性癫痫发作。这些研究的结果应该提供洞察氧化应激是否与AS相关，它如何影响海马突触可塑性，海马依赖性记忆和AS中其他形式的神经功能障碍，以及使用靶向抗氧化剂是否可能是治疗AS个体的可行疗法。

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.