Abstract
Altered expression of the E3 ubiquitin ligase UBE3A, which is involved in protein degradation through the proteasome-mediated pathway, is associated with neurodevelopmental and behavioral defects observed in Angelman syndrome (AS) and autism. However, little is known about the neuronal function of UBE3A and the pathogenesis of UBE3A-associated disorders. To understand the in vivo function of UBE3A in the nervous system, we generated multiple mutations of ube3a, the Drosophila ortholog of UBE3A. We found a significantly increased number of total boutons and satellite boutons in conjunction with compromised endocytosis in the neuromuscular junctions (NMJs) of ube3a mutants compared to the wild type. Genetic and biochemical analysis showed upregulation of bone morphogenetic protein (BMP) signaling in the nervous system of ube3a mutants. An immunochemical study revealed a specific increase in the protein level of Thickveins (Tkv), a type I BMP receptor, but not other BMP receptors Wishful thinking (Wit) and Saxophone (Sax), in ube3a mutants. Ube3a was associated with and specifically ubiquitinated lysine 227 within the cytoplasmic tail of Tkv, and promoted its proteasomal degradation in Schneider 2 cells. Negative regulation of Tkv by Ube3a was conserved in mammalian cells. These results reveal a critical role for Ube3a in regulating NMJ synapse development by repressing BMP signaling. This study sheds new light onto the neuronal functions of UBE3A and provides novel perspectives for understanding the pathogenesis of UBE3A-associated disorders.
Highlights
Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe mental retardation, developmental delay, ataxia, seizures, speech impairment, and happy disposition [1, 2]
Angelman syndrome (AS), characterized by severe mental retardation, developmental delay, ataxia, seizures, speech impairment, and happy disposition, is caused by mutation of E3 ubiquitin ligase ubiquitin protein ligase E3A (UBE3A); a critical enzyme involved in proteasome-mediated protein
Using Drosophila melanogaster as a model system in conjunction with an array of biochemical and physiological assays, we showed that mutants of ube3a had excess synaptic boutons and endocytic defects at the neuromuscular junction terminals due to an elevated level of bone morphogenetic protein (BMP) signaling
Summary
Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe mental retardation, developmental delay, ataxia, seizures, speech impairment, and happy disposition [1, 2] It is caused by disruption of the ubiquitin protein ligase E3A (UBE3A), which is expressed in the brain primarily from the maternal allele as a result of tissue-specific genomic imprinting [3, 4]. A point mutation of UBE3A identified in an autism proband disrupts its phosphorylation by protein kinase A and increases its ligase activity [8] Both loss and gain of UBE3A function are associated with neurodevelopmental and cognitive defects. Abnormal development and function of excitatory synapses in conjunction with a reduced number of AMPA receptors in Ube3a mutant mice are attributed to decreased Ube3a-mediated proteasomal degradation of RhoA guanine exchange factor (GEF) Ephexin and synaptic protein Arc [19, 20]. The molecular mechanisms by which UBE3A regulates synapse development and function remain unclear
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