Identification of Neuronal Substrates of Angelman Syndrome Ligase

描述(申请人提供)：Angelman综合征(AS)是一种罕见的遗传性疾病，会导致严重的精神发育迟滞和一系列其他认知、运动和行为症状。UBE3A基因突变导致泛素连接酶E6-AP(E6相关蛋白)功能障碍。虽然UBE3A基因产物在广泛的组织中被发现，但它的表达特定地印记在大脑中的一部分神经元中。到目前为止，大多数患者的突变都扰乱了E6-AP的催化活性或与同源E2s结合的能力，这意味着E3连接酶功能的破坏肯定是AS发生的关键。我们假设E6-AP在该疾病中的功能障碍会导致UPS功能受损，导致关键的、未知的底物在疾病发病机制中发挥关键作用的异常神经元堆积。我们建议鉴定和验证候选的E6-AP底物。这是单一多效性基因破坏的结果，导致严重的精神发育迟滞和一系列额外的、毁灭性的症状。识别由于蛋白质加工缺陷而积累的E6-AP底物是确定AS中被破坏的分子通路的关键的第一步，并可能导致AS和其他相关疾病的治疗方法的发展。公共卫生相关性：与老龄化人口的认知、运动和行为相关的神经退行性问题正在成为日益沉重的负担。我们认为，以这些过程中的共同缺陷为特征的Angelman综合征(AS)是由于蛋白质加工缺陷导致的未知蛋白质的异常积累所致。尽管AS的遗传缺陷自1997年以来就已为人所知，但这些累积的蛋白质的身份仍不清楚。我们建议寻找AS中被破坏的分子和途径，这可能导致针对更常见的神经退行性变症状的治疗。

DESCRIPTION (provided by applicant): Angelman syndrome (AS) is a rare genetic disorder that results in severe mental retardation and a host of other cognitive, movement, and behavioral symptoms. Mutations in the UBE3A gene lead to dysfunction of the ubiquitin ligase, E6-AP (E6 associated protein). While the UBE3A gene product is found in a broad range of tissues, its expression is specifically imprinted in a subset of neurons in brain. The majority of patient mutations identified to date perturb E6-AP's catalytic activity or capacity to associate with cognate E2s, implying that disruption of its E3 ligase function must be critical to the development of AS. We hypothesize that dysfunction of E6-AP in the disorder causes impaired UPS function, leading to abnormal neuronal accumulations of crucial, unidentified substrates that play a critical role in disease pathogenesis. We propose to identify and verify candidates that are E6-AP substrates. AS is the consequence of disruption of a single pleiotropic gene, resulting in profound mental retardation and a host of additional, devastating symptoms. Identification of E6-AP substrates that accumulate due to defective protein processing is a critical first step to determine the molecular pathways disrupted in AS, and could lead to the development of treatments for it and other related disorders. PUBLIC HEALTH RELEVANCE: Neurodegenerative problems associated with cognition, movement, and behavior of the aging population are becoming an increasing burden. We propose that Angelman Syndrome (AS), which is characterized by shared defects in these processes, results from abnormal accumulation of unidentified proteins caused by defective protein processing. Although the genetic defect underlying AS has been known since 1997, the identity of these accumulated proteins remains unknown. We propose to find the molecules and pathways that are disrupted in AS, which may lead to therapies to target more common symptoms of neurodegeneration.