Regulation of Synaptic Structure by Ubiquitin C-Terminal Hydrolase L1

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 monomericubiquitin.Conversely,pharmacologicalinhibitionofUCH-L1significantlyreducesmonomericubiquitinlevelsandcausesdramatic 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.

Ubiquitin carboxyl-terminal hydrolase L1 is required for maintaining the structure and function of the neuromuscular junction

“…Additionally, the synaptic transmission impairment we observed in UCH-L1 −/− mice seems similar to that produced in shibire mutants (39,43). Several lines of evidence suggest that UCH-L1 is involved in stabilizing the level of ubiquitin in neurons (5,44). Because ubiquitin plays a critical role in endocytosis of membrane proteins (45), it is conceivable that in the absence of UCH-L1, synapses fail to maintain normal levels of ubiquitin required for vesicle endocytosis or vesicle regeneration after endocytosis.…”

Role of the ubiquitin–proteasome system in brain ischemia: Friend or foe?

“…Restoring free ubiquitin levels prevented the early death at 8 weeks of age, body weight loss and presynaptic dysfunction observed in the ataxic mice (Chen et al, 2011). The deficit in neurotransmitter release in the ax J mice is in accordance with the results showing that inhibition of Uch-L1, another DUB abundantly expressed in neurons, also decreases free ubiquitin levels, thus increasing the number of synaptic vesicles (Cartier et al, 2009). Mutations in the RING finger E3 ligase Listerin, observed in the lister mouse model, also induce biochemical, cellular and neurological alterations similar to those observed in many neurodegenerative processes, including deficits in balance and motor coordination, dystrophic neurites, swollen mitochondria, reduced number and caliber of motor neurons and hyperphosphorylated Tau .…”

“…These effects were promoted by Rpt6 phosphorylation on the serine 120 residue by CaMKIIa Djakovic et al, 2012), and prevented by CaMKII inhibition or by knocking down CaMKIIa with iRNA (Bingol et al, 2010). Similarly, activation of NMDAR also stimulates the Ubiquitin C-terminal Hydrolase L1 (UCH-L1), thereby increasing free monomeric ubiquitin levels (Cartier et al, 2009). This contrasts with the results obtained using light-controlled excitation of individual presynaptic terminals of hippocampal neurons, which increased polyubiquitin conjugation but was without effect on the redistribution of free ubiquitin and proteasomes .…”

Do Low Serum UCH-L1 and TDP-43 Levels Indicate Disturbed Ubiquitin- Proteosome System in Autism Spectrum Disorder?

“…UCH-L1 and the UPS molecule are thought to be essential for synaptic function and cognition (27,28,29). Altered ubiquitination resulting from abnormal UCH-L1 expression may contribute to learning and memory impairment (30).…”