UCHL1

The UCHL1 gene provides instructions for making an enzyme called ubiquitin carboxyl-terminal esterase L1. This enzyme is found in nerve cells throughout the brain. Ubiquitin carboxyl-terminal esterase L1 is probably involved in the cell machinery that breaks down (degrades) unwanted proteins. In cells, damaged or excess proteins are tagged with molecules called ubiquitin. Ubiquitin serves as a signal to move these unwanted proteins into specialized structures known as proteasomes, where the proteins are degraded. The ubiquitin-proteasome system acts as the cell's quality control system by disposing of damaged, misshapen, and excess proteins.

Although the exact function of ubiquitin carboxyl-terminal esterase L1 is not fully understood, it appears to have two enzyme activities. One activity, called hydrolase, removes and recycles ubiquitin molecules from degraded proteins. This recycling step is important to sustain the degradation process. The other enzyme activity, known as ligase, links together ubiquitin molecules for use in tagging proteins for disposal.

Parkinson disease - associated with the UCHL1 gene

A normal variation (polymorphism) in the UCHL1 gene appears to reduce the risk of developing Parkinson disease, particularly in young adults. This variation leads to a change in one of the building blocks (amino acids) used to make the UCHL1 enzyme. Instead of serine at position 18 in the enzyme's chain of amino acids, people with the protective polymorphism have the amino acid tyrosine (written as Ser18Tyr or S18Y). This particular variation is very common in Chinese and Japanese populations and occurs less frequently in European populations. The polymorphism reduces the ligase activity of the UCHL1 enzyme but has little effect on the hydrolase activity. It remains unclear how this amino acid variation protects against Parkinson disease.

By contrast, a particular mutation in the UCHL1 gene may increase the risk of Parkinson disease. A single UCHL1 mutation has been reported in two siblings with this disease. The mutation replaces the amino acid isoleucine with the amino acid methionine at position 93 in the UCHL1 enzyme (written as Ile93Met or I93M). The mutation leads to decreased hydrolase activity, which may disrupt the ubiquitin-proteasome system. Instead of being degraded, unwanted proteins may accumulate to toxic levels that impair or kill nerve cells in the brain. It is unclear whether this mutation is a cause of Parkinson disease, because it has been identified in only a single family.