A Role for the Ubiquitin–Proteasome System in Activity-Dependent Presynaptic Silencing

Jiang, Xiaoping; Litkowski, Patricia; Taylor, Amanda; Lin, Ying; Snider, B. Joy; Moulder, Krista L.

doi:10.1523/jneurosci.4965-09.2010

Cited by 77 publications

(120 citation statements)

References 58 publications

(116 reference statements)

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“…These data strongly support a role for RIM in regulating presynaptic strength during homeostatic adaptation to activity silencing. Accordingly, Jiang et al (2010) demonstrated the downregulation of RIM levels in persistently presynaptically silent synapses emerging upon prolonged tonic depolarization and that overexpression of RIM1 completely prevented induction of presynaptic silencing.…”

Section: Discussionmentioning

confidence: 94%

Extensive Remodeling of the Presynaptic Cytomatrix upon Homeostatic Adaptation to Network Activity Silencing

Lazarevic

Schöne²,

Heisenberg³

et al. 2011

Journal of Neuroscience

121

172

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Global changes of activity in neuronal networks induce homeostatic adaptations of synaptic strengths, which involve functional remodeling of both presynaptic and postsynaptic apparatuses. Despite considerable advances in understanding cellular properties of homeostatic synaptic plasticity, the underlying molecular mechanisms are not fully understood. Here, we explored the hypothesis that adaptive homeostatic adjustment of presynaptic efficacy involves molecular remodeling of the release apparatus including the presynaptic cytomatrix, which spatially and functionally coordinates neurotransmitter release. We found significant downregulation of cellular expression levels of presynaptic scaffolding proteins Bassoon, Piccolo, ELKS/CAST, Munc13, RIM, liprin-␣, and synapsin upon prolonged (48 h) activity depletion in rat neuronal cultures. This was accompanied by a general reduction of Bassoon, Piccolo, ELKS/CAST, Munc13, and synapsin levels at synaptic sites. Interestingly, RIM was upregulated in a subpopulation of synapses. At the level of individual synapses, RIM quantities correlated well with synaptic activity, and a constant relationship between RIM levels and synaptic activity was preserved upon silencing. Silencing also induced synaptic enrichment of other previously identified regulators of presynaptic release probability, i.e., synaptotagmin1, SV2B, and P/Q-type calcium channels. Seeking responsible cellular mechanisms, we revealed a complex role of the ubiquitin-proteasome system in the functional presynaptic remodeling and enhanced degradation rates of Bassoon and liprin-␣ upon silencing. Together, our data indicate a significant molecular reorganization of the presynaptic release apparatus during homeostatic adaptation to network inactivity and identify RIM, synaptotagmin1, Ca v 2.1, and SV2B as molecular candidates underlying the main silencing-induced functional hallmark at presynapse, i.e., increase of neurotransmitter release probability.

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Section: Discussionmentioning

confidence: 94%

Extensive Remodeling of the Presynaptic Cytomatrix upon Homeostatic Adaptation to Network Activity Silencing

Lazarevic

Schöne²,

Heisenberg³

et al. 2011

Journal of Neuroscience

121

172

View full text Add to dashboard Cite

show abstract

“…Another study, however, found a decrease in Rim 1 and Munc 13 during persistent presynaptic silencing induced by depolarization (Jiang et al 2010). The results from these two studies seem to be at odds with each other even though both used postnatal rat hippocampal neurons in culture and antibodies against Rim 1 and Munc 13 from the same commercial sources.…”

Section: Presynaptic Roles Of the Uppmentioning

confidence: 96%

“…The results from these two studies seem to be at odds with each other even though both used postnatal rat hippocampal neurons in culture and antibodies against Rim 1 and Munc 13 from the same commercial sources. Perhaps the discrepancy was due to the fact that the study by Jiang et al (2010) measured Rim 1 and Munc 13 after K+-induced depolarization, whereas the study by Rinetti and Schweizer (2010) tested Rim 1 and Munc 13 levels in relation to changes in mEPSCs and spontaneous EPSCs. Therefore, it is likely that the degradation of Rim 1 and Munc 13 is triggered by neuronal depolarization rather than baseline activity.…”

Section: Presynaptic Roles Of the Uppmentioning

confidence: 99%

The ubiquitin-proteasome pathway and synaptic plasticity

Hegde¹

2010

Learn. Mem.

129

123

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Proteolysis by the ubiquitin-proteasome pathway (UPP) has emerged as a new molecular mechanism that controls wideranging functions in the nervous system, including fine-tuning of synaptic connections during development and synaptic plasticity in the adult organism. In the UPP, attachment of a small protein, ubiquitin, tags the substrates for degradation by a multisubunit complex called the proteasome. Linkage of ubiquitin to protein substrates is highly specific and occurs through a series of well-orchestrated enzymatic steps. The UPP regulates neurotransmitter receptors, protein kinases, synaptic proteins, transcription factors, and other molecules critical for synaptic plasticity. Accumulating evidence indicates that the operation of the UPP in neurons is not homogeneous and is subject to tightly managed local regulation in different neuronal subcompartments. Investigations on both invertebrate and vertebrate model systems have revealed local roles for enzymes that attach ubiquitin to substrate proteins, as well as for enzymes that remove ubiquitin from substrates. The proteasome also has been shown to possess disparate functions in different parts of the neuron. Here I give a broad overview of the role of the UPP in synaptic plasticity and highlight the local roles and regulation of the proteolytic pathway in neurons.

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“…In the nervous system, the UPS regulates several aspects of synaptic function, such as spinogenesis (Hamilton et al, 2012), presynaptic neurotransmission (Willeumier et al, 2006;Jiang et al, 2010), long-term potentiation (Dong et al, 2008;Cajigas et al, 2010;Pavlopoulos et al, 2011), synaptic scaling , apical dendrite outgrowth/ polarization (Hamilton and Zito, 2013;Miao et al, 2013;Vadhvani et al, 2013), dendritic arborization (Puram et al, 2013), axon growth (Yang et al, 2013), and synapse formation and elimination (Yi and Ehlers, 2007).…”

Section: Role Of Ups In Nervous Systemmentioning

confidence: 99%

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

Caldeira

Salazar

Curcio

et al. 2014

Progress in Neurobiology

113

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A B S T R A C TThe ubiquitin-proteasome system (UPS) is a catalytic machinery that targets numerous cellular proteins for degradation, thus being essential to control a wide range of basic cellular processes and cell survival. Degradation of intracellular proteins via the UPS is a tightly regulated process initiated by tagging a target protein with a specific ubiquitin chain. Neurons are particularly vulnerable to any change in protein composition, and therefore the UPS is a key regulator of neuronal physiology. Alterations in UPS activity may induce pathological responses, ultimately leading to neuronal cell death. Brain ischemia triggers a complex series of biochemical and molecular mechanisms, such as an inflammatory response, an exacerbated production of misfolded and oxidized proteins, due to oxidative stress, and the breakdown of cellular integrity mainly mediated by excitotoxic glutamatergic signaling. Brain ischemia also damages protein degradation pathways which, together with the overproduction of damaged proteins and consequent upregulation of ubiquitin-conjugated proteins, contribute to the accumulation of ubiquitincontaining proteinaceous deposits. Despite recent advances, the factors leading to deposition of such aggregates after cerebral ischemic injury remain poorly understood. This review discusses the current knowledge on the role of the UPS in brain function and the molecular mechanisms contributing to UPS dysfunction in brain ischemia with consequent accumulation of ubiquitin-containing proteins. Chemical inhibitors of the proteasome and small molecule inhibitors of deubiquitinating enzymes, which promote the degradation of proteins by the proteasome, were both shown to provide neuroprotection in brain ischemia, and this apparent contradiction is also discussed in this review. ß

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A Role for the Ubiquitin–Proteasome System in Activity-Dependent Presynaptic Silencing

Cited by 77 publications

References 58 publications

Extensive Remodeling of the Presynaptic Cytomatrix upon Homeostatic Adaptation to Network Activity Silencing

Extensive Remodeling of the Presynaptic Cytomatrix upon Homeostatic Adaptation to Network Activity Silencing

The ubiquitin-proteasome pathway and synaptic plasticity

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

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