Identification of Neuronal Substrates of Angelman Syndrome Ligase

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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.