The ubiquitin-proteasome pathway and synaptic plasticity

Hegde, Ashok N.

doi:10.1101/lm.1504010

Cited by 131 publications

(129 citation statements)

References 140 publications

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“…Moreover, our biochemical data show that UPS-dependent degradation is controlled by the activity status and contributes to remodeling of synaptic protein complexes in a highly substrate-specific manner. The target specificity of UPSdependent degradation is ascribed to the high selectivity of ubiquitin-ligating enzyme complexes for their targets (Hegde, 2010). Therefore, we suggest that the regulated ubiquitin conjugation to presynaptic scaffolds might control their differential activity status-dependent degradation by UPS observed in our experiments.…”

Section: Discussionmentioning

confidence: 71%

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

Lazarevic

Schöne²,

Heisenberg³

et al. 2011

Journal of Neuroscience

122

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: 71%

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

Lazarevic

Schöne²,

Heisenberg³

et al. 2011

Journal of Neuroscience

122

172

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“…result of alteration in protein synthesis and/or protein degradation. Formation of long-term memory is dependent on both phenomena (38). The major changes in de novo protein synthesis appear hours after induction of long-term plasticity (15,35).…”

Section: Resultsmentioning

confidence: 99%

“…Studies over the last decade demonstrate strong links between maintenance of long-term potentiation (LTP, a type of long-term synaptic plasticity) and protein degradation ((37); for review, see (38)). It was recently shown that inhibition of the proteasome system may enhance LTP induction (39) because of prevention of translation activator targeting (40).…”

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confidence: 99%

Dynamics of Hippocampal Protein Expression During Long-term Spatial Memory Formation

Borovok

Nesher

Levin

et al. 2016

Molecular & Cellular Proteomics

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Spatial memory depends on the hippocampus, which is particularly vulnerable to aging. This vulnerability has implications for the impairment of navigation capacities in older people, who may show a marked drop in performance of spatial tasks with advancing age. Contemporary understanding of long-term memory formation relies on molecular mechanisms underlying long-term synaptic plasticity. With memory acquisition, activity-dependent changes occurring in synapses initiate multiple signal transduction pathways enhancing protein turnover. This enhancement facilitates de novo synthesis of plasticity related proteins, crucial factors for establishing persistent long-term synaptic plasticity and forming memory engrams. Extensive studies have been performed to elucidate molecular mechanisms of memory traces formation; however, the identity of plasticity related proteins is still evasive. In this study, we investigated protein turnover in mouse hippocampus during long-term spatial memory formation using the reference memory version of radial arm maze (RAM) paradigm. We identified 1592 proteins, which exhibited a complex picture of expression changes during spatial memory formation. Variable linear decomposition reduced significantly data dimensionality and enriched three principal factors responsible for variance of memory-related protein levels at (1) the initial phase of memory acquisition (165 proteins), (2) during the steep learning improvement (148 proteins), and (3) the final phase of the learning curve (123 proteins). Gene ontology and signaling pathways analysis revealed a clear correlation between memory improvement and learning phasecurbed expression profiles of proteins belonging to specific functional categories. We found differential enrichment of (1) Long-term synaptic plasticity is considered a cellular correlate of long-term memory (LTM) 1 . Contemporary understanding of memory formation is based on the initiation and maintenance of long-term synaptic plasticity (1-4), for which de novo protein synthesis is a vital requirement. De novo protein synthesis itself is secondary to activity-dependent changes in synapses that occur during learning processes. These activity changes trigger post-translational modifications of proteins initiating and sustaining multiple signal transduction pathways. In turn, these signaling pathways regulate changes in synaptic strength and connectivity by governing gene expression and protein translation (5-13). Depending on time elapsed since triggering of long-term synaptic plasticity, protein synthesis may be limited to the dendrites directly involved in the plasticity processes (14 -18). Multiple synaptic From the ‡Department

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“…We observed that UCH-L1 is a target of oxidative damage in DS and DS/AD brains, and its oxidative modification likely leads to a decreased function as demonstrated by activity assay [80,81]. One of the major consequences of aberrant UCH-L1 activity is an impaired proteasome proteolytic system, which will lead to accumulation of damaged proteins and formation of protein aggregates [20,97,[115][116][117]. To confirm this hypothesis we measured the trypsin-like, chymotrypsin-like, and caspaselike activities of the proteasome demonstrating decreased levels that suggest a reduced activity of UPS in DS brain [81].…”

Section: Oxidative Damage To Proteostasis Network In Dsmentioning

confidence: 99%

Oxidative Stress and Proteostasis Network: Culprit and Casualty of Alzheimer’s-Like Neurodegeneration

Domenico

Head

Butterfield

et al. 2014

Advances in Geriatrics

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Free radical-mediated damage to proteins is particularly important in aging and age-related neurodegenerative diseases, because in the majority of cases it is a non-reversible phenomenon that requires clearance systems for removal. Major consequences of protein oxidation are loss of protein function and the formation of large protein aggregates, which are often toxic to cells if allowed to accumulate. Deposition of aggregated, misfolded, and oxidized proteins may also result from the impairment of protein quality control (PQC) system, including protein unfolded response, proteasome, and autophagy. Perturbations of such components of the proteostasis network that provides a critical protective role against stress conditions are emerging as relevant factor in triggering neuronal death. In this outlook paper, we discuss the role of protein oxidation as a major contributing factor for the impairment of the PQC regulating protein folding, surveillance, and degradation. Recent studies from our group and from others aim to better understand the link between Down syndrome and Alzheimer's disease neuropathology. We propose oxidative stress and alteration of proteostasis network as a possible unifying mechanism triggering neurodegeneration.

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The ubiquitin-proteasome pathway and synaptic plasticity

Cited by 131 publications

References 140 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

Dynamics of Hippocampal Protein Expression During Long-term Spatial Memory Formation

Oxidative Stress and Proteostasis Network: Culprit and Casualty of Alzheimer’s-Like Neurodegeneration

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