Regulation of synaptic structure by ubiquitin C-terminal hydrolase L1.
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.
Cartier
Anna E
AE
Section of Neurobiology, Department of Biological Sciences, University of California, San Diego, La Jolla, California 92093-0347, USA.
Djakovic
Stevan N
SN
Salehi
Afshin
A
Wilson
Scott M
SM
Masliah
Eliezer
E
Patrick
Gentry N
GN
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D003712:Dendrites / Q000378:metabolism / Q000648:ultrastructure; D000076122:Disks Large Homolog 4 Protein; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D051528:Guanylate Kinases; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007189:Indans / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission / Q000379:methods; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016202:N-Methylaspartate; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010091:Oximes / Q000494:pharmacology; D013347:Subcellular Fractions / Q000378:metabolism / Q000648:ultrastructure; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*
D015763:2-Amino-5-phosphonovalerate; D000076122:Disks Large Homolog 4 Protein; D004791:Enzyme Inhibitors; D018683:Excitatory Amino Acid Agents; D049452:Green Fluorescent Proteins; D051528:Guanylate Kinases; D007189:Indans; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D016202:N-Methylaspartate; D010091:Oximes; D025801:Ubiquitin; D043222:Ubiquitin Thiolesterase; C542094:4,5,6,7-tetrachloroindan-1,3-dione; C501447:Dlg4 protein, mouse; C525086:LDN 57444; C079240:Mtap2 protein, mouse; C526917:UCHL3 protein, mouse; C485184:enhanced green fluorescent protein; C496976:Uchl1 protein, mouse