Roles of UBE3A-mediated p18 regulation in synaptogenesis and synaptic plasticity

点击翻译按钮获取中文摘要

UBE3A, an E3 ligase in the ubiquitin-proteasomal system, plays important roles in brain development and function. Optimal CNS UBE3A expression is crucial since its deficiency results in Angelman syndrome (AS), while its over- expression increases the risk for autism. Yet, the precise function of UBE3A in the CNS remains largely unknown. In AS mouse models, Ube3a deficiency leads to deficits in motor function, learning and memory, and social interactions. We have recently reported that Ube3a deficiency leads to increased activation of mTORC1 but decreased activation of mTORC2, the two core complexes in the mechanistic target of rapamycin (mTOR) signaling pathway. However, how UBE3A deficiency results in mTORC1 over-activation remains unknown. Emerging evidence indicates that the presence of amino acids is essential for full mTORC1 activation. Amino acid-induced mTORC1 activation depends on the recruitment of mTORC1 to late endosomal/lysosomal membranes, a process involving the formation of heterodimers of a RagA or RagB, with a RagC or RagD through binding to the Ragulator. The anchoring of Ragulator to lysosomal membrane is through one of its components, p18. Myristoylation and palmitoylation in the N-terminal domain of p18 are critical for its lysosomal localization. Our preliminary results revealed that p18 levels were increased as a result of Ube3a deficiency in COS1 cells and in AS mouse brain. We further showed that p18 could be ubiquitinated by Ube3a in COS1 cells. These findings led us to propose the central hypothesis that, under normal conditions, lysosomal localized p18 levels are controlled by Ube3a-mediated ubiquitination, which targets p18 for proteasomal degradation. A correlate of this hypothesis is that lack of Ube3a-mediated p18 ubiquitination and degradation in AS mice results in imbalanced mTORC1/mTORC2 signaling and abnormal spine morphology and synaptic plasticity. We will first identify the ubiquitination sites in p18 and determine whether N-terminal acylation affects Ube3a- mediated p18 ubiquitination. We will then determine whether Ube3a-mediated p18 regulation plays important roles in synaptogenesis, synaptic plasticity, and experience-dependent remodeling of synapses using a multidisciplinary approach. Since both UBE3A deficiency and overexpression are linked to neurodevelopmental disorders, understanding UBE3A-mediated regulation of p18 and of mTOR signaling and its role in synaptogenesis and synaptic plasticity should shed light on basic neurobiological mechanisms, as well as on several neurological and neuropsychiatric diseases.