Identification of Neuronal Substrates of Angelman Syndrome Ligase

描述（由申请人提供）：安吉曼综合征（AS）是一种罕见的遗传性疾病，导致严重的精神发育迟滞和其他认知，运动和行为症状的主机。UBE 3A基因突变导致泛素连接酶E6-AP（E6相关蛋白）功能障碍。虽然UBE 3A基因产物存在于广泛的组织中，但其表达特异性地印刻在大脑中的神经元亚群中。迄今为止，大多数患者突变干扰E6-AP的催化活性或与同源E2相关的能力，这意味着其E3连接酶功能的破坏对AS的发展至关重要。我们假设E6-AP功能障碍导致UPS功能受损，导致神经元异常积累的关键，身份不明的底物，在疾病的发病机制中发挥关键作用。我们建议识别和验证候选人是E6-AP底物。AS是单一多效性基因破坏的结果，导致严重的智力迟钝和一系列额外的破坏性症状。鉴定由于蛋白质加工缺陷而积累的E6-AP底物是确定AS中破坏的分子途径的关键第一步，并可能导致其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越来越大的负担。我们提出，Angelman综合征（AS），这是其特征在于共享的缺陷，在这些过程中，结果从异常积累的未知蛋白质所造成的蛋白质加工缺陷。虽然自1997年以来，AS的遗传缺陷已经被发现，但这些积累的蛋白质的身份仍然未知。我们建议找到在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疾病症状的治疗。

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.