This new application focuses on the determination of the mechanism by which loss of UBE3A leads to synaptic dysfunction. Based on extensive prior findings, our overall hypothesis is that UBE3A operates to regulate levels of substrate proteins important for neural development, and that disruption of UBE3A activity leads to inappropriately high levels of these substrates, causing the neuronal dysfunctions observed in Angelman Syndrome (AS). The proposed studies are designed to provide improved understanding of the link between aberrations of UBE3A signaling and AS phenotypes. As a long-term goal, our findings will aid in the development of novel approaches for pharmacological manipulation of mis-regulated UBE3A substrates, resulting in new and innovative approaches for the treatment of AS, and possibly other non-syndromic autistic disorders. Specifically:
Aim 1. To determine the contribution of elevated Ephexin5 levels to AS- associated phenotypes, to test the hypothesis that elevated Ephexin5 expression in Ube3a mutant mice result in AS-associated synaptic and behavioral phenotypes;
Aim 2. To determine the molecular mechanisms controlling UBE3A-mediated Ephexin5 ubiquitination, to test the hypothesis that distinct protein sequences on Ephexin5 and additional cofactors spatially and temporally control UBE3A mediated ubiquitination of Ephexin5;
Aim 3. To identify neural substrates of UBE3A, to test the hypothesis that additional UBE3A substrates participate in the etiology of AS.
The proposed studies are designed to understand at the molecular level the functions and regulation of the ubiquitin ligase, UBE3A, in the context of synapse biogenesis and Angelman Syndrome etiology. The successful completion of this work will provide new insights into the molecular mechanisms of UBE3A substrates in the brain. Given the high prevalence between cytogenetic abnormalities associated with the UBE3A gene and cognitive disorders, any advancement in our understanding of the molecular mechanisms mediating UBE3A dependent brain development promises to improve pharmacological approaches for the treatment of individuals with cognitive impairment.
|Ramachandran, Kapil V; Fu, Jack M; Schaffer, Thomas B et al. (2018) Activity-Dependent Degradation of the Nascentome by the Neuronal Membrane Proteasome. Mol Cell 71:169-177.e6|
|Sell, Gabrielle L; Schaffer, Thomas B; Margolis, Seth S (2017) Reducing expression of synapse-restricting protein Ephexin5 ameliorates Alzheimer's-like impairment in mice. J Clin Invest 127:1646-1650|
|Ramachandran, Kapil V; Margolis, Seth S (2017) A mammalian nervous-system-specific plasma membrane proteasome complex that modulates neuronal function. Nat Struct Mol Biol 24:419-430|
|Sell, Gabrielle L; Margolis, Seth S (2015) From UBE3A to Angelman syndrome: a substrate perspective. Front Neurosci 9:322|