Regulation of synaptic structure by ubiquitin C-terminal hydrolase L1.

Academic Article


  • 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.
  • Keywords

  • 2-Amino-5-phosphonovalerate, Animals, Animals, Newborn, Cells, Cultured, Dendrites, Disks Large Homolog 4 Protein, Enzyme Inhibitors, Excitatory Amino Acid Agents, Gene Expression Regulation, Green Fluorescent Proteins, Guanylate Kinases, Hippocampus, Humans, Indans, Indoles, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Mice, Mice, Knockout, Microscopy, Electron, Transmission, Microtubule-Associated Proteins, N-Methylaspartate, Neurons, Oximes, Subcellular Fractions, Synapses, Synaptic Transmission, Transfection, Ubiquitin, Ubiquitin Thiolesterase
  • Digital Object Identifier (doi)

    Author List

  • Cartier AE; Djakovic SN; Salehi A; Wilson SM; Masliah E; Patrick GN
  • Start Page

  • 7857
  • End Page

  • 7868
  • Volume

  • 29
  • Issue

  • 24