The ubiquitin C-terminal hydrolase L1 (UCH-L1) is a member of a family of de-ubiquitinating enzymes that can generate free ubiquitin from ubiquitin precursors via its ubiquitin ligase activity. By associating with free ubiquitin, it also prevents its degradation. Neuronal UCH-L1 has been linked to Parkinson’s disease, the development of tumors, and neuropathic pain. LDN-57444 is an inhibitor of UCH-L1 activity (IC50 = 0.88, Ki = 0.4 μM) that demonstrates selectivity for UCH-L1 compared to UCH-L3 (IC50 = 25 μM). Loss of UCH-L1 activity causes cell death through the apoptosis pathway due to an impaired ubiquitin-proteasome pathway. LDN-57444-induced reduction of free ubiquitin has been shown to create dramatic alterations in synaptic structure and function, increasing spine size while decreasing spine density in hippocampal neurons.
