Ubiquitin carboxyl-terminal hydrolase L1 is required for maintaining the structure and function of the neuromuscular junction.
The enzyme ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) is one of the most abundant proteins in the mammalian nervous system. In humans, UCH-L1 is also found in the ubiquitinated inclusion bodies that characterize neurodegenerative diseases in the brain, suggesting its involvement in neurodegeneration. The physiologic role of UCH-L1 in neurons, however, remains to be further elucidated. For example, previous studies have provided evidence both for and against the role of UCH-L1 in synaptic function in the brain. Here, we have characterized a line of knockout mice deficient in the UCH-L1 gene. We found that, in the absence of UCH-L1, synaptic transmission at the neuromuscular junctions (NMJs) is markedly impaired. Both spontaneous and evoked synaptic activity are reduced; paired pulse-facilitation is impaired, and synaptic transmission fails to respond to high-frequency, repetitive stimulation at the NMJs of UCH-L1 knockout mice. Morphologic analyses of the NMJs further revealed profound structural defects-loss of synaptic vesicles and accumulation of tubulovesicular structures at the presynaptic nerve terminals, and denervation of the muscles in UCH-L1 knockout mice. These findings demonstrate that UCH-L1 is required for the maintenance of the structure and function of the NMJ and that the loss of normal UCH-L1 activity may result in neurodegeneration in the peripheral nervous system.
Chen
Fujun
F
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Sugiura
Yoshie
Y
Myers
Kalisa Galina
KG
Liu
Yun
Y
Lin
Weichun
W
D000818:Animals; D018450:Disease Progression; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009154:Mutation; D009469:Neuromuscular Junction / Q000166:cytology* / Q000201:enzymology*; D010243:Paralysis / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009435:Synaptic Transmission; D043222:Ubiquitin Thiolesterase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D043222:Ubiquitin Thiolesterase; C496976:Uchl1 protein, mouse