Roles of ubiquitination at the synapse

Abstract

The ubiquitin proteasome system (UPS) was first described as a mechanism for protein degradation more than three decades ago, but the critical roles of the UPS in regulating neuronal synapses have only recently begun to be revealed. Targeted ubiquitination of synaptic proteins affects multiple facets of the synapse throughout its life cycle; from synaptogenesis and synapse elimination to activity-dependent synaptic plasticity and remodeling. The recent identification of specific UPS molecular pathways that act locally at the synapse illustrates the exquisite specificity of ubiquitination in regulating synaptic protein trafficking and degradation events. Synaptic activity has also been shown to determine the subcellular distribution and composition of the proteasome, providing additional mechanisms for locally regulating synaptic protein degradation. Together these advances reveal that tight control of protein turnover plays a conserved, central role in establishing and modulating synapses in neural circuits.

Fbxo45, a Novel Ubiquitin Ligase, Regulates Synaptic Activity

“…Moreover, recent studies have identified several additional mammalian E3s at the synaptic site, including SCRAPPER (9), Siah (24,25), Staring (26), and Parkin (27). Although ample evidence supports the role of protein ubiquitination in synaptic development and plasticity in vertebrates (28), the specific molecular mechanisms underlying these effects remain to be elucidated.…”

The nonsense-mediated decay pathway maintains synapse architecture and synaptic vesicle cycle efficacy

“…Other mRNA-binding proteins, such as fragile-X mental retardation protein (FMRP), similarly have crucial roles in the regulation of synaptic mRNA stability, trafficking and translation (Gatto and Broadie, 2008;Pan and Broadie, 2007;Pan et al, 2004;Pan et al, 2008;Repicky and Broadie, 2009;Tessier and Broadie, 2008;Zhang et al, 2001;Zhang et al, 2005). Moreover, local protein degradation via the ubiquitin proteasome system (UPS) has also recently been established as a key mechanism that shapes synaptic structural development, neurotransmission strength and synaptic plasticity (Haas and Broadie, 2008;Haas et al, 2007a;Haas et al, 2007b;Speese et al, 2003).…”

“…At the synapse, FMRP has several functions, including the control of axonal and dendritic arbor size, bouton number and distribution, transmission strength, postsynaptic glutamate receptor trafficking and the regulation of presynaptic vesicle pools (Gatto and Broadie, 2008;Pan and Broadie, 2007;Pan et al, 2008;Pan et al, 2004;Repicky and Broadie, 2009;Tessier and Broadie, 2008;Zhang et al, 2001;Zhang et al, 2005). In balance with translation regulation, UPSmediated degradation has dynamic functions that control synapse architecture, neurotransmission strength and synaptic protein abundance, including postsynaptic glutamate receptors (Haas and Broadie, 2008;Haas et al, 2007a;Speese et al, 2003). The ubiquitin ligase highwire acts to restrict synaptic overgrowth by down-regulating the MAPKKK-Wallenda pathway, where mutants exhibit increased neuromuscular junction (NMJ) branch and bouton numbers (Wan et al, 2000;Wu et al, 2007).…”

Activity-dependent Protein Dynamics Define Interconnected Cores of Co-regulated Postsynaptic Proteins

“…Active transport mechanisms exist and have been well characterized for AMPA-type glutamate receptors (AMPA-Rs) 1 via either insertion into the synapse or tighter association with the postsynaptic density (PSD) following lateral diffusion within the cell membrane (2). In addition to AMPA-Rs, other proteins known to be subject to activity-dependent regulation include calcium calmodulin-dependent protein kinase II alpha and beta, NMDA-type glutamate receptors (NMDA-Rs), and proteosome subunits (3)(4)(5). Synaptic protein content is dysregulated in a number of neuropsychiatric and neurodegenerative diseases, including Alzheimer's disease and fragile X mental retardation (6 -8).…”