The Ubiquitin Proteasome System Acutely Regulates Presynaptic Protein Turnover and Synaptic Efficacy

Speese, Sean D.; Trotta, Nick; Rodesch, Chris K.; Aravamudan, Bharathi; Broadie, Kendal

doi:10.1016/s0960-9822(03)00338-5

Cited by 218 publications

(207 citation statements)

References 60 publications

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“…Other studies also observed decreases in mitochondrial related genes in pyramidal neurons in the DLPFC of schizophrenia subjects (39, 40). Metabolic systems are strongly linked to the control of synaptic protein connectivity, signaling, and turnover (41-45). Thus, decreases in mitochondrial function coupled with abnormal glucose utilization in neurons could reduce the capacity of pyramidal cells to sustain a normal complement of dendritic spines, contributing to the lower DLPFC spine density reported in schizophrenia (38, 46, 47).…”

Section: Discussionmentioning

confidence: 99%

Neuron-specific deficits of bioenergetic processes in the dorsolateral prefrontal cortex in schizophrenia

et al. 2018

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Schizophrenia is a devastating illness that affects over 2 million people in the U.S. and costs society billions of dollars annually. New insights into the pathophysiology of schizophrenia are needed to provide the conceptual framework to facilitate development of new treatment strategies. We examined bioenergetic pathways in the dorsolateral prefrontal cortex (DLPFC) of subjects with schizophrenia and control subjects using western blot analysis, quantitative real-time polymerase chain reaction, and enzyme/substrate assays. Laser-capture microdissection-qPCR was used to examine these pathways at the cellular level. We found decreases in hexokinase (HXK) and phosphofructokinase (PFK) activity in the DLPFC, as well as decreased PFK1 mRNA expression. In pyramidal neurons, we found an increase in monocarboxylate transporter 1 mRNA expression, and decreases in HXK1, PFK1, glucose transporter 1 (GLUT1), and GLUT3 mRNA expression. These results suggest abnormal bioenergetic function, as well as a neuron-specific defect in glucose utilization, in the DLPFC in schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Neuron-specific deficits of bioenergetic processes in the dorsolateral prefrontal cortex in schizophrenia

et al. 2018

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“…Cite this article as Cold Spring Harb Perspect Biol 2010;2:a001925 contexts during neuronal development, including: axonal pruning (Watts et al 2004); various aspects of axon guidance (Campbell and Holt 2001;DiAntonio et al 2001;Bloom et al 2007;Lewcock et al 2007); synapse formation (DiAntonio et al 2001;Nakata et al 2005); synapse maintenance (DiAntonio et al 2001;Aravamudan and Broadie 2003;Ehlers 2003;Speese et al 2003); and synapse elimination (Ding et al 2007) (reviewed in DiAntonio and Hicke 2004). Acute treatment with the proteosome inhibitor lactacystin blocks axogenesis in dorsal root ganglion cells (Klimaschewski et al 2006).…”

Section: Initiating and Growing An Axonmentioning

confidence: 99%

Initiating and Growing an Axon

Polleux¹,

Snider²

2010

Cold Spring Harbor Perspectives in Biology

163

127

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The ability of neurons to form a single axon and multiple dendrites underlies the directional flow of information transfer in the central nervous system. Dendrites and axons are molecularly and functionally distinct domains. Dendrites integrate synaptic inputs, triggering the generation of action potentials at the level of the soma. Action potentials then propagate along the axon, which makes presynaptic contacts onto target cells. This article reviews what is known about the cellular and molecular mechanisms underlying the ability of neurons to initiate and extend a single axon during development. Remarkably, neurons can polarize to form a single axon, multiple dendrites, and later establish functional synaptic contacts in reductionist in vitro conditions. This approach became, and remains, the dominant model to study axon initiation and growth and has yielded the identification of many molecules that regulate axon formation in vitro (Dotti et al. 1988). At present, only a few of the genes identified using in vitro approaches have been shown to be required for axon initiation and outgrowth in vivo. In vitro, axon initiation and elongation are largely intrinsic properties of neurons that are established in the absence of relevant extracellular cues. However, the importance of extracellular cues to axon initiation and outgrowth in vivo is emerging as a major theme in neural development (Barnes and Polleux 2009). In this article, we focus our attention on the extracellular cues and signaling pathways required in vivo for axon initiation and axon extension.

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“…Mutant subunits act in a dominant negative manner to interfere with proteasome function; in multiple previous studies, they have been shown to inhibit UPS-mediated degradation of known proteasome substrates (Schweisguth, 1999;Speese et al, 2003;Neuburger et al, 2006). Transgenic co-expression of both proteasome subunit mutants in the Drosophila eye using the UAS-GAL4 system has a synergistic effect (Belote JM and Fortier, 2002).…”

Section: Resultsmentioning

confidence: 99%

“…Transgenic co-expression of both proteasome subunit mutants in the Drosophila eye using the UAS-GAL4 system has a synergistic effect (Belote JM and Fortier, 2002). Previously, it was shown in our laboratory that the proteasome is highly localized at the Drosophila NMJ synapse and that presynaptic inhibition of proteasome function rapidly leads to changes in synaptic transmission that are likely mediated through degradation of the synaptic vessel priming protein DUNC-13 Speese et al, 2003). To examine the effect of inhibiting proteasome function specifically in the postsynaptic cell, we crossed the double-mutant UAS-DTS5, DTS7 line with the muscle-specific MHC-GAL4 line to drive expression of the DTS proteasome mutant subunits specifically in muscle (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Using the Drosophila NMJ glutamatergic synapse, we have shown previously that the UPS regulates presynaptic release probability via the acute regulation of the dUNC-13 synaptic vesicle priming protein, regulated downstream of G-protein coupled receptor PKA-and PLCdependent pathways (Aravamudan et al, 1999;Aravamudan and Broadie, 2003;Speese et al, 2003). Postsynaptically, five GluR subunits (GluRIIA-E) share homology to mammalian AMPA/kainate ionotropic GluRs in mammals (Petersen et al, 1997;Marrus et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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The ubiquitin–proteasome system postsynaptically regulates glutamatergic synaptic function

Haas

Miller

Friedman

et al. 2007

Molecular and Cellular Neuroscience

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The ubiquitin proteasome system (UPS) actively controls protein dynamics and local abundance via regulated protein degradation. This study investigates UPS roles in the regulation of postsynaptic function and molecular composition in the Drosophila neuromuscular junction (NMJ) genetic system. To specifically impair UPS function postsynaptically, the UAS/GAL4 transgenic method was employed to drive postsynaptic expression of proteasome β2 and β6 subunit mutant proteins, which operate through a dominant negative mechanism to block proteasome function. When proteasome mutant subunits were constitutively expressed, excitatory junctional current (EJC) amplitudes were increased, demonstrating that postsynaptic proteasome function limits neurotransmission strength. Interestingly, the alteration in synaptic strength was calcium-dependent and miniature EJCs had significantly smaller mean amplitudes and more rapid mean decay rates. Postsynaptic levels of the Drosophila PSD-95/SAP97 homologue, discs large (DLG), and the GluRIIB-containing glutamate receptor were increased, but GluRIIA-containing receptors were unaltered. With acute postsynaptic proteasome inhibition using an inducible transgenic system, neurotransmission was similarly elevated with the same specific increase in postsynaptic GluRIIB abundance. These findings demonstrate postsynaptic proteasome regulation of glutamatergic synaptic function that is mediated through specific regulation of GluRIIB-containing glutamate receptors.

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The Ubiquitin Proteasome System Acutely Regulates Presynaptic Protein Turnover and Synaptic Efficacy

Abstract: Taken together, these studies demonstrate that the UPS functions locally within synaptic boutons to acutely control levels of presynaptic protein and that the rate of UPS-dependent protein degradation is a primary determinant of neurotransmission strength.

Cited by 218 publications

References 60 publications

Neuron-specific deficits of bioenergetic processes in the dorsolateral prefrontal cortex in schizophrenia

Neuron-specific deficits of bioenergetic processes in the dorsolateral prefrontal cortex in schizophrenia

Initiating and Growing an Axon

The ubiquitin–proteasome system postsynaptically regulates glutamatergic synaptic function

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