Local ubiquitin-proteasome-mediated proteolysis and long-term synaptic plasticity

Abstract

The ubiquitin-proteasome pathway (UPP) of protein degradation has many roles in synaptic plasticity that underlies memory. Work on both invertebrate and vertebrate model systems has shown that the UPP regulates numerous substrates critical for synaptic plasticity. Initial research took a global view of ubiquitin-protein degradation in neurons. Subsequently, the idea of local protein degradation was proposed a decade ago. In this review, we focus on the functions of the UPP in long-term synaptic plasticity and discuss the accumulated evidence in support of the idea that the components of the UPP often have disparate local roles in different neuronal compartments rather than a single cell-wide function.

Keywords: learning and memory; proteasome; protein degradation; ubiquitin; ubiquitin conjugation.

FIGURE 1

Differential local roles of the proteasome in dendrites and in the nucleus during L-LTP. (A) Proteasome Active: the proteasome in dendrites is highly active, translational activators such as eIF4E are degraded (broken green spheres) and protein substrates that positively regulate L-LTP are degraded (broken spheres). Therefore extent of L-LTP is limited and only normal L-LTP ensues. A retrograde signal is likely transmitted to the nucleus. Proteasome aids transcription of genes by degrading the CREB repressor ATF4 (broken squares in the nucleus) thus allowing for normal L-LTP maintenance. Transcribed mRNAs (triangles) travel to activated synapses. (B) Proteasome Inactive: when the proteasome is inhibited (indicated by X marks on the proteasome), translational activators are stabilized (intact green spheres) leading to increased protein synthesis in dendrites. Also the newly synthesized proteins in dendrites are stabilized (intact spheres) and L-LTP-inducing stimulation protocols dramatically increase (upward arrow) the early part of L-LTP (Ep-L-LTP). Proteasome inhibition obstructs CREB-mediated transcription by preventing the degradation of transcription repressor ATF4 (intact squares in the nucleus). Proteasome inhibition could also inhibit the generation of the retrograde signal. Therefore, L-LTP is not maintained but decays (downward arrow). Proteasome inhibition also causes failure of sustained translation because of stabilization of translation repressors such as 4E-BP (intact red spheres) which accumulate after induction of L-LTP thus contributing to blockade of L-LTP maintenance. [Modified from Hegde (2010) and reprinted with permission from Cold Spring Harbor Laboratory Press].