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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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2-Amino-5-phosphonovalerate / pharmacology
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Animals
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Animals, Newborn
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Cells, Cultured
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Dendrites / metabolism
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Dendrites / ultrastructure
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Disks Large Homolog 4 Protein
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Enzyme Inhibitors / pharmacology
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Excitatory Amino Acid Agents / pharmacology
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Green Fluorescent Proteins / genetics
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Guanylate Kinases
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Hippocampus / cytology
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Humans
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Indans / pharmacology
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Indoles / pharmacology
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Intracellular Signaling Peptides and Proteins / metabolism
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Membrane Proteins / metabolism
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Mice
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Mice, Knockout
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Microscopy, Electron, Transmission / methods
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Microtubule-Associated Proteins / metabolism
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N-Methylaspartate
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Neurons / cytology
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Neurons / drug effects
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Neurons / metabolism
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Oximes / pharmacology
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Subcellular Fractions / metabolism
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Subcellular Fractions / ultrastructure
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Synapses / drug effects
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Synapses / metabolism
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Synapses / physiology*
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Synapses / ultrastructure
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Synaptic Transmission / drug effects
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Synaptic Transmission / physiology*
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Transfection
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Ubiquitin / genetics
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Ubiquitin / metabolism
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Ubiquitin Thiolesterase / antagonists & inhibitors
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Ubiquitin Thiolesterase / deficiency
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Ubiquitin Thiolesterase / metabolism*
Substances
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4,5,6,7-tetrachloroindan-1,3-dione
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Disks Large Homolog 4 Protein
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Dlg4 protein, mouse
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Enzyme Inhibitors
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Excitatory Amino Acid Agents
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Indans
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Indoles
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Intracellular Signaling Peptides and Proteins
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LDN 57444
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Membrane Proteins
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Microtubule-Associated Proteins
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Mtap2 protein, mouse
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Oximes
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UCHL3 protein, mouse
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Ubiquitin
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Ubiquitin carboxyl-Terminal Hydrolase L-1, mouse
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enhanced green fluorescent protein
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Green Fluorescent Proteins
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N-Methylaspartate
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2-Amino-5-phosphonovalerate
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Guanylate Kinases
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Ubiquitin Thiolesterase