Ubiquitin carboxy-terminal hydrolase L1 (, ubiquitin C-terminal hydrolase, UCH-L1) is a deubiquitinating enzyme. Function UCH-L1 is a member of a gene family whose products hydrolyze small C-terminal adducts of ubiquitin to generate the ubiquitin monomer. Expression of UCH-L1 is highly specific to neurons and to cells of the diffuse neuroendocrine system and their tumors. It is abundantly present in all neurons (accounts for 1-2% of total brain protein), expressed specifically in neurons and testis/ovary. The catalytic triad of UCH-L1 contains a cysteine at position 90, an aspartate at position 176, and a histidine at position 161 that are responsible for its hydrolase activity. Relevance to neurodegenerative disorders A point mutation (I93M) in the gene encoding this protein is implicated as the cause of Parkinson's disease in one German family, although this finding is controversial, as no other Parkinson's disease patients with this mutation have been found. Furthermore, a polymorphism (S18Y) in this gene has been found to be associated with a reduced risk for Parkinson's disease. This polymorphism has specifically been shown to have antioxidant activity. Another potentially protective function of UCH-L1 is its reported ability to stabilize monoubiquitin, an important component of the ubiquitin proteasome system. It is thought that by stabilizing the monomers of ubiquitin and thereby preventing their degradation, UCH-L1 increases the available pool of ubiquitin to be tagged onto proteins destined to be degraded by the proteasome. The gene is also associated with Alzheimer's disease, and required for normal synaptic and cognitive function. Loss of Uchl1 increases the susceptibility of pancreatic beta-cells to programmed cell death, indicating that this protein plays a protective role in neuroendocrine cells and illustrating a link between diabetes and neurodegenerative diseases. Patients with early-onset neurodegeneration in which the causative mutation was in the UCHL1 gene (specifically, the ubiquitin binding domain, E7A) display blindness, cerebellar ataxia, nystagmus, dorsal column dysfunction, and upper motor neuron dysfunction. Ectopic expression Although UCH-L1 protein expression is specific to neurons and testis/ovary tissue, it has been found to be expressed in certain lung-tumor cell lines. This abnormal expression of UCH-L1 is implicated in cancer and has led to the designation of UCH-L1 as an oncogene. Furthermore there is evidence that UCH-L1 might play a role in the pathogenesis of membranous glomerulonephritis as UCH-L1 de novo expression in podocytes was seen in PHN, the rat model of human mGN. This UCH-L1 expression is thought to induce at least