Regulation of synaptic structure by ubiquitin C-terminal hydrolase L1

Anna E. Cartier, Stevan N. Djakovic, Afshin Salehi, Scott M. Wilson, Eliezer Masliah, Gentry N. Patrick

Research output: Contribution to journalArticlepeer-review

103 Scopus citations

Abstract

Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a deubiquitinating enzyme that is selectively and abundantly expressed in the brain, and its activity is required for normal synaptic function. Here, we show that UCH-L1 functions in maintaining normal synaptic structure in hippocampal neurons. We found that UCH-L1 activity is rapidly upregulated by NMDA receptor activation, which leads to an increase in the levels of free monomeric ubiquitin. Conversely, pharmacological inhibition of UCH-L1 significantly reduces monomeric ubiquitin levels and causes dramatic alterations in synaptic protein distribution and spine morphology. Inhibition of UCH-L1 activity increases spine size while decreasing spine density. Furthermore, there is a concomitant increase in the size of presynaptic and postsynaptic protein clusters. Interestingly, however, ectopic expression of ubiquitin restores normal synaptic structure in UCH-L1-inhibited neurons. These findings point to a significant role of UCH-L1 in synaptic remodeling, most likely by modulating free monomeric ubiquitin levels in an activity-dependent manner.

Original languageEnglish (US)
Pages (from-to)7857-7868
Number of pages12
JournalJournal of Neuroscience
Volume29
Issue number24
DOIs
StatePublished - Jun 17 2009
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)

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