Ubiquitin Carboxyl-terminal Esterase L1 (UCH-L1), also known as PGP 9.5, is a deubiquitinating enzyme with a predicted molecular weight of 25 kDa. The human protein shares 95% amino acid sequence identity with its mouse and rat orthologs. UCH-L1 is expressed abundantly in neurons, accounting for 1-2% of total soluble proteins in the brain. It localizes primarily to the cytoplasm, but a subpopulation has been shown to be transiently nuclear. UCH-L1 contains two catalytic residues, Cys90 and His161, which are required for isopeptide bond cleavage at the C-terminal glycine residue of Ubiquitin. The levels of free Ubiquitin appear to be partially regulated by UCH-L1 through the hydrolysis of small Ubiquitin chains and the stabilization of monomeric Ubiquitin. Mice lacking functional UCH-L1 show neuronal dysfunction and neurodegeneration, and mutations in this enzyme have been linked to Parkinson’s disease, suggesting that it is important for proper central nervous system function. UCH-L1 also likely plays a complex role in cancer. It has been reported to function as an oncogene in lymphoma, colorectal cancer, and nonsmall cell lung carcinoma. In contrast, it is thought to function as a tumor suppressor protein in nasopharyngeal and breast cancers.