Subcellular organization of UBE3A in neurons

Abstract

Ubiquitination regulates a broad array of cellular processes, and defective ubiquitination is implicated in several neurological disorders. Loss of the E3 ubiquitin-protein ligase UBE3A causes Angelman syndrome. Despite its clinical importance, the normal role of UBE3A in neurons is still unclear. As a step toward deciphering its possible functions, we performed high-resolution light and electron microscopic immunocytochemistry. We report a broad distribution of UBE3A in neurons, highlighted by concentrations in axon terminals and euchromatin-rich nuclear domains. Our findings suggest that UBE3A may act locally to regulate individual synapses, while also mediating global, neuron-wide influences through the regulation of gene transcription. KeywordsAngelman syndrome; E6-AP; ubiquitin-proteasome pathway; axon terminal; mitochondria; euchromatin; heterochromatin; RRID:nif-0000-30467; RRID:AB_10740376The ubiquitin-proteasome pathway, which provides a mechanism for protein degradation in eukaryotes, is important for a broad array of basic cellular processes. Neurons have long dendrites and axons whose distal regions are remote from the soma, emphasizing the importance of local protein synthesis and degradation in neuronal function. Accordingly, the ubiquitin-proteasome pathways has been shown to be important for appropriate circuit wiring, neuronal morphogenesis, intracellular trafficking, and synaptic plasticity (Hegde, * Correspondence to: Benjamin D. Philpot, bphilpot@med.unc.edu, Richard J. Weinberg, richard.weinberg@gmail.com. Conflict of interest statementAuthors verify that they have no known or potential conflict of interest including any financial, personal, or other relationships with other people or organizations within 3 years of beginning the submitted work that could inappropriately influence, or be perceived to influence, this work. 2004;Acconcia et al., 2009;Cajigas et al., 2010;Schwarz and Patrick, 2012;Hamilton and Zito, 2013;Goo et al., 2015). Conversely, dysregulation of the ubiquitin-proteasome system has been implicated in multiple neurological disorders including Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, and autism (Tai and Schuman, 2008;Schwarz and Patrick, 2012). HHS Public AccessThe covalent attachment of ubiquitin to protein substrates involves sequential reactions catalyzed by a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), and a ubiquitin-protein ligase (E3). The E3 ligases largely dictate specificity and target protein recognition for the ubiquitin conjugation system; thus the biology of E3 ligases is of broad biological and clinical importance. Based on their distinct domains and mode of action, E3 proteins segregate into three families: RING/RING-like E3s, RING-in-between-RING (RBR) E3s, and Homologous to the E6-AP Carboxyl Terminus (HECT) E3s. The loss of expression or function of UBE3A (also called E6-AP), the founding member of the HECT E3 ligase family, leads to Angelman syndrome (AS), a severe n...

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“…1J). We therefore concluded that a large portion of UBE3A molecules was localized in the nucleus of neurons, which is consistent with the results of a recent study (35).…”

Abnormalities of synaptic mitochondria in autism spectrum disorder and related neurodevelopmental disorders

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A novel UBE3A sequence variant identified in eight related individuals with neurodevelopmental delay, results in a phenotype which does not match the clinical criteria of Angelman syndrome

“…Mice express two protein isoforms, isoforms 2 and 3, which are highly homologous to the human isoforms 3 and 1, respectively (Avagliano Trezza et al, 2019; Greer et al, 2010). In human and mouse neurons UBE3A is mainly localized to the nucleus with smaller amounts present in axons and dendrites (Avagliano Trezza et al, 2019; Burette et al, 2016, 2018; Dindot, Antalffy, Bhattacharjee, & Beaudet, 2008). Recent work in mice has revealed how this subcellular distribution of UBE3A is achieved: the short isoform (mUBE3A Iso3), which constitutes ~80% of total UBE3A, is mainly nuclear while the, less abundant, long isoform (mUBE3AIso2) is predominantly present in the cytosol (Avagliano Trezza et al, 2019; Miao et al, 2013).…”