Synaptic protein degradation by the ubiquitin proteasome system

doi:10.1016/j.conb.2005.08.016

Current Opinion in Neurobiology

Volume 15, Issue 5, October 2005, Pages 536-541

https://doi.org/10.1016/j.conb.2005.08.016 Get rights and content

Synaptic plasticity — the modulation of synaptic strength between a presynaptic terminal and a postsynaptic dendrite — is 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.

Introduction

Most proteins in a cell are degraded by the ubiquitin–proteasome system (UPS). The target protein is marked for degradation by the attachment of a chain of ubiquitin molecules (polyubiquitin chain). This chain is then recognized by a protein complex called the proteasome, which also carries the enzymatic activities that degrade the target protein. The initial attachment of the polyubiquitin chain to the target protein occurs through a series of enzymatic steps that provide substrate specificity. Delivery of the polyubiquitinated proteins to the proteasome and the final degradation of the protein are also highly regulated events. Collectively, the UPS enzymes are known as E1 (ubiquitin-activating enzyme), E2s (ubiquitin-conjugating enzymes) and E3s (ubiquitin ligases). The UPS can be regulated at each enzymatic step, ensuring that the right protein is degraded at the right time. The polyubiquitin chain can be removed or its length can be modulated by deubiquitinating enzymes (DUBs), providing reversibility to the ubiquitination reaction. Readers should refer to recent reviews that detail the enzymatic machinery of the UPS [1, 2, 3].

Section snippets

Localization

The proteasome has been studied most extensively in yeast, in which it plays a key role in the control of the cell cycle. In yeast, some of the UPS enzymes have been identified, as have the proteasome subunits and accessory proteins [4]. In neurons, some of the components of the UPS have been observed in dendrites and near synapses [5, 6, 7]. The presence of two main components of the UPS, ubiquitin and proteasome subunits, has been demonstrated at synapses and in the postsynaptic density PSD

Presynaptic targets

A few studies have begun to shed light on the function of UPS in presynaptic nerve terminals. Speese et al. [34] have shown that components of UPS (E1 and the proteasome) are present in presynaptic boutons at the Drosophila neuro-muscular junction (NMJ). They have also shown that the proteasome is active at these boutons by expressing a conditional fluorescent reporter of proteasome activity. Inhibiting the proteasome caused a 50% increase in evoked excitatory junctional current (EJC) amplitude

Postsynaptic targets

The trafficking of ionotropic glutamate receptors — namely AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate) and NMDA (N-methyl-D-aspartate) receptors — has become an intense area of research in recent years as techniques for examining receptor trafficking have offered a glimpse of the dynamics that might underlie some forms of plasticity [43]. The stability of AMPA and NMDA receptors (GluRs and NMDARs) on the postsynaptic membrane is regulated dynamically. For example, GluRs undergo

Conclusions

In recent years, UPS biology at the synapse has become an area of intense research. The UPS shares features with other better established synaptic regulatory systems, namely phosphorylation and local protein synthesis. Modulating protein function by post-translational modification and changing the protein content can achieved by UPS, through ubiquitination and protein degradation, respectively. The studies described above point to the importance of UPS on both sides of the synapse. However,

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest
•• of outstanding interest

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Synaptic protein degradation by the ubiquitin proteasome system

Introduction

Section snippets

Localization

Presynaptic targets

Postsynaptic targets

Conclusions

References and recommended reading

Biochim Biophys Acta

Biochim Biophys Acta

Curr Biol

Neurosci Lett

Cell

Curr Biol

Neuron

Proc Natl Acad Sci USA

Nature

Cell

Neuron

Nat Genet

J Biol Chem

Proc Natl Acad Sci USA

Mol Cell Proteomics

Mol Cell

Plant Cell Physiol

Glia

Neuron

Curr Top Microbiol Immunol

Curr Biol

Neuron

Proc Natl Acad Sci USA

Cell

Arch Pathol