Ubiquitin-Proteasome System Inhibition Promotes Long-Term Depression and Synaptic Tagging/Capture (original) (raw)
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Synaptic protein degradation by the ubiquitin proteasome system
Current Opinion in Neurobiology, 2005
Synaptic plasticity-the modulation of synaptic strength between a presynaptic terminal and a postsynaptic dendriteis thought to be a mechanism that underlies learning and memory. It has become increasingly clear that regulated protein synthesis is an important mechanism used to regulate the protein content of synapses that results in changes in synaptic strength. Recent experiments have highlighted a role for the opposing process, that is, regulated protein degradation via the ubiquitin-proteasome system, in synaptic plasticity. These recent findings raise exciting questions as to how proteasomal activity can regulate synapses over different temporal and spatial scales.
The ubiquitin proteasome system functions as an inhibitory constraint on synaptic strengthening
Current biology : CB, 2003
Long-lasting forms of synaptic plasticity have been shown to depend on changes in gene expression. Although many studies have focused on the regulation of transcription and translation during learning-related synaptic plasticity, regulated protein degradation provides another common means of altering the macromolecular composition of cells. We have investigated the role of the ubiquitin proteasome system in long-lasting forms of learning-related plasticity in Aplysia sensory-motor synapses. We find that inhibition of the proteasome produces a long-lasting (24 hr) increase in synaptic strength between sensory and motor neurons and that it dramatically enhances serotonin-induced long-term facilitation. The increase in synaptic strength produced by proteasome inhibitors is dependent on translation but not transcription. In addition to the increase in synaptic strength, proteasome inhibition leads to an increase in the number of synaptic contacts formed between the sensory and motor neu...
The ubiquitin-proteasome cascade is required for mammalian long-term memory formation
European Journal of Neuroscience, 2001
It has been recently demonstrated that ubiquitin±proteasome-mediated proteolysis is required for long-term synaptic facilitation in Aplysia. Here we show that the hippocampal blockade of this proteolytic pathway is also required for the formation of long-term memory in the rat. Bilateral infusion of lactacystin, a speci®c proteasome inhibitor, to the CA1 region caused full retrograde amnesia for a one-trial inhibitory avoidance learning when given 1, 4 or 7h, but not 10 h, after training. Proteasome inhibitor I produced similar effects. In addition, inhibitory avoidance training resulted in an increased ubiquitination and 26S proteasome proteolytic activity and a decrease in the levels of IkappaB, a substrate of the ubiquitin±proteasome cascade, in hippocampus 4 h after training. Together, these ®ndings indicate that the ubiquitin±proteasome cascade is crucial for the establishment of LTM in the behaving animal.
The Ubiquitin Proteasome System Acutely Regulates Presynaptic Protein Turnover and Synaptic Efficacy
Current Biology, 2003
East ubiquitin ligase (E3) to attach ubiquitin to an internal University of Utah lysine residue of the substrate protein ( ). Sub-Salt Lake City, Utah 84112-0840 strate specificity is typically attributed to the ubiquitin 2 Department of Biological Sciences ligase, which can recognize various signals including Vanderbilt University primary sequence and posttranslational modifications VU Station B to regulate ubiquitylation of the substrate. Attachment Box 351634 of ubiquitin to cellular proteins can serve as a signal for Nashville, Tennessee 37235-1634 a growing number of biological processes, including degradation by the proteasome or endocytosis and trafficking to the lysosomal pathway. The tightly regulated Summary cascade controlling protein degradation via the proteasome has pivotal regulatory roles in a wide spectrum of Background: The ubiquitin proteasome system (UPS) cellular processes, ranging from cell cycle control to mediates regulated protein degradation and provides a modulation of the immune response. Therefore, it is surmechanism for closely controling protein abundance in prising that little work has been done to investigate putaspatially restricted domains within cells. We hypothetive functional roles of the (UPS) in the mature nervous sized that the UPS may acutely determine the local consystem, particularly in the regulation of the complex centration of key regulatory proteins at neuronal synprotein cycles that acutely modulate the efficacy of synapses as a means for locally modulating synaptic aptic transmission. efficacy and the strength of neurotransmission commu-Recent work has begun to reveal roles for ubiquitinnication. dependent processes in neuronal development, espe-Results: We investigated this hypothesis at the Drocially during synapse formation and modulation. In Drosophila neuromuscular synapse by using an array of sophila, ubiquitin conjugation triggers the endocytosis genetic and pharmacological tools. This study demonof signaling proteins with key guidance functions in axostrates that UPS components are present in presynaptic nal pathfinding [1]. At the Drosophila neuromuscular boutons and that the UPS functions locally in the presynjunction (NMJ), both functional and anatomical synaptic aptic compartment to rapidly eliminate a conditional development is regulated by a balance between ubiquitransgenic reporter of proteasome activity. We assayed tylation and de-ubiquitylation [2]. Recent studies of C. a panel of synaptic proteins to determine whether the elegans central synapses have shown that ubiquitin is UPS acutely regulates the local abundance of native also involved in the endocytosis and possible degradasynaptic targets. Both acute pharmacological inhibition tion of the glutamate receptor subunit GLR-1 at postsynof the proteasome (Ͻ1 hr) and targeted genetic perturaptic sites [3].The authors propose that this mechanism bation of proteasome function in the presynaptic neuron may regulate the strength of synaptic transmission; mucause the specific accumulation of the essential synaptations that decrease GLR-1 ubiquitylation also increase tic vesicle-priming protein DUNC-13. Most importantly, locomotory activity. These Drosophila and C. elegans acute pharmacological inhibition of the proteasome (Ͻ1 studies clearly demonstrate that ubiquitin-dependent hr) causes a rapid strengthening of neurotransmission mechanisms play vital roles in synapses, most particu-(an approximately 50% increase in evoked amplitude) larly in regulating endocytosis to control protein traffickbecause of increased presynaptic efficacy. The proing to and from the plasma membrane. However, the teasome-dependent regulation of presynaptic protein direct involvement of proteasomal protein degradation abundance, both of the exogenous reporter and native in regulating these synaptic mechanisms is unclear. DUNC-13, and the modulation of presynaptic neuro-In addition to developmental functions, the UPS has transmitter release occur on an intermediate, rapid tens also been implicated in the manifestation of long-term of minutes) timescale. synaptic plasticity. Recent studies in Aplysia synapses Conclusions: Taken together, these studies demonhave demonstrated that transition from short-term facilistrate that the UPS functions locally within synaptic boutation (STF) to long-term facilitation (LTF) depends on tons to acutely control levels of presynaptic protein and proteasome-mediated protein degradation [4]. Similarly, that the rate of UPS-dependent protein degradation is in rat synapses the transition from short-term potentiaa primary determinant of neurotransmission strength. tion (STP) to long-term potentiation (LTP) requires UPS function in the hippocampus [5]. Null mutations in the Introduction E3 ubiquitin ligase E6-AP prevent this synaptic plasticity transition in mouse hippocampal neurons [6]. To date, The attachment of ubiquitin to substrate proteins is aconly a few synaptic proteins have been identified as complished via a regulated cascade of enzymes beginsubstrates of ubiquitin attachment; ␣-synuclein [7], synphilin [8], and CDCrel-1 [9] are ubiquitylated by the ubi-Correspondence: kendal.broadie@vanderbilt.edu Current Biology 900
The effects of proteasomal inhibition on synaptic proteostasis
Synaptic function crucially depends on uninterrupted synthesis and degradation of synaptic proteins. While much has been learned on synaptic protein synthesis, little is known on the routes by which synaptic proteins are degraded. Here we systematically studied how inhibition of the ubiquitin-proteasome system (UPS) affects the degradation rates of thousands of neuronal and synaptic proteins. We identified a group of proteins, including several proteins related to glutamate receptor trafficking, whose degradation rates were significantly slowed by UPS inhibition. Unexpectedly, however, degradation rates of most synaptic proteins were not significantly affected. Interestingly, many of the differential effects of UPS inhibition were readily explained by a quantitative framework that considered known metabolic turnover rates for the same proteins. In contrast to the limited effects on protein degradation, UPS inhibition profoundly and preferentially suppressed the synthesis of a large number of synaptic proteins. Our findings point to the importance of the UPS in the degradation of certain synaptic proteins, yet indicate that under basal conditions most synaptic proteins might be degraded through alternative pathways.
The ubiquitin-specific protease 14 (USP14) is a critical regulator of long-term memory formation
Learning & Memory, 2013
Numerous studies have suggested a role for ubiquitin–proteasome-mediated protein degradation in learning-dependent synaptic plasticity; however, very little is known about how protein degradation is regulated at the level of the proteasome during memory formation. The ubiquitin-specific protease 14 (USP14) is a proteasomal deubiquitinating enzyme that is thought to regulate protein degradation in neurons; however, it is unknown if USP14 is involved in learning-dependent synaptic plasticity. We found that infusion of a USP14 inhibitor into the amygdala impaired long-term memory for a fear conditioning task, suggesting that USP14 is a critical regulator of long-term memory formation in the amygdala.
Neurobiology of Learning and Memory, 2015
Healthy neuronal function and synaptic modification require a concert of synthesis and degradation of proteins. Increasing evidence indicates that protein turnover mediated by proteasome activity is involved in long-term synaptic plasticity and memory. However, its role in different phases of memory remains debated, and previous studies have not examined the possible requirement of protein degradation in recognition memory. Here, we show that the proteasome inhibitor, lactacystin (LAC), infused into the CA1 area of the hippocampus at two specific time points during consolidation, impairs 24-retention of memory for object recognition in rats. Administration of LAC after retrieval did not affect retention. These findings provide the first evidence for a requirement of proteasome activity in recognition memory, indicate that protein degradation in the hippocampus is necessary during selective time windows of memory consolidation, and further our understanding of the role of protein turnover in memory formation.
2019
Dynamic control of protein degradation via the ubiquitin proteasome system is thought to play a crucial role in neuronal function and synaptic plasticity. The proteasome subunit Rpt6, an AAA ATPase subunit of the 19S regulatory particle, has emerged as an important site for regulation of 26S proteasome function in neurons. Phosphorylation of Rpt6 on serine 120 (S120) can stimulate the catalytic rate of substrate degradation by the 26S proteasome and this site is targeted by the plasticity-related kinase calcium/calmodulin-dependent kinase II (CaMKII), making it an attractive candidate for regulation of proteasome function in neurons. Several in vitro studies have shown that altered Rpt6 S120 phosphorylation can affect the structure and function of synapses. To evaluate the importance of Rpt6 S120 phosphorylation in vivo, we created two mouse models which feature mutations at S120 that block or mimic phosphorylation at this site. We find that peptidase and ATPase activities are upreg...