Ubiquitin C-terminal hydrolase 1 (UCHL1) has several other names, such as ubiquitin carboxyl esterase L1, ubiquitin thiolesterase, PGP9.5 and Park5. It was originally identified as a major component of the neuronal cytoplasm from 2-dimensional gel analysis of brain tissues, and was given the name protein gene product 9.5 or PGP9.5 (1). It is claimed to represent 1-2% of total brain protein but is localized only in the cytoplasm of neurons (1, 2). It was later found that a ubiquitin C-terminal hydrolase enzyme activity was associated with the PGP9.5 protein, resulting in the renaming of PGP9.5 to UCHL1.
UCHL1 was the first of a family of ubiquitin C-terminal hydrolases which have been characterized, many of which also have rigid cell type specific expression patterns. The ubiquitin C-terminal hydrolases cleave ubiquitin from other molecules and this activity is important to generate mono-ubiquitin from the several genes which encode polyubiquitin chains or ubiquitin fused to other proteins. The activity is also important to remove ubiquitin from partially degraded proteins, allowing the ubiquitin monomer to be recycled. Regulation of the ubiquitin pathway is very important and many disease states are associated with defects in this pathway. For example the Park5 gene causes one form of human Parkinson’s disease, and proves to be a point mutations in the UCHL1 gene producing a I93M form of the UCHL1 protein which has reduced ubiquitin hydrolase activity (3). Interestingly, a common allelic variant of UCHL1, the S18Y polymorphism is actually protective against Parkinson’s disease. Recent studies suggest that UCHL1 also has a ubiqutinyl ligase activity, being able to couple ubiquitin monomers by linking the C-terminus of one with lysine 63 of the other (3).
Since UCHL1 is heavily expressed in neurons, antibodies to UCHL1 can be used to identify neurons in histological sections and in tissue culture. The great abundance of this protein in neurons means that it is released from neurons in large amounts following injury or degeneration, so the detection of UCHL1 in CSF and other bodily fluids can be used as a biomarker of neuronal injury or degeneration. Antibody was raised in mouse against recombinant full length human UCHL1 purified from E. coli. The HGNC name for this protein is UCHL1.
Immunofluorescent analysis of cortical neuron-glial culture from E20 rat stained with mouse mAb to UCHL1, MCA-BH7, dilution 1:5,000 in green, and costained with chicken pAb to GFAP, CPCA-GFAP, dilution 1:5,000 in red. The blue is DAPI staining of nuclear DNA. The MCA-BH7 antibody stains cell bodies and dendrites of neurons, while the GFAP antibody labels astrocytes. Mouse select image for larger view.
1. Doran JF, Jackson P, Kynoch PA, Thompson RJ. Isolation of PGP 9.5, a new human neurone-specific protein detected by high-resolution two-dimensional electrophoresis J Neurochem. 40:1542-7 (1983).2. Wilkinson KD, et al. The neuron-specific protein PGP 9.5 is a ubiquitin carboxyl-terminal hydrolase. Science 246:670-3 (1989).3. Kurihara LJ, Kikuchi T, Wada K, Tilghman SM. Loss of Uch-L1 and Uch-L3 leads to neurodegeneration, posterior paralysis and dysphagia. Hum. Mol. Genet. 10:1963-70 (2001).4. Maraganore DM, et al. UCHL1 is a Parkinson’s disease susceptibility gene. Ann Neurol. 55:512-21 (2004).5. Bilguvar K, et al. Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration. PNAS 110:3489-94 (2013).6. Liu Y, et al. The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson’s disease susceptibility. Cell 111:209-18 (2002).7. Leroy E, et al. The ubiquitin pathway in Parkinson’s disease. Nature 395:451-2 (1998).8. Day IN, Thompson RJ. UCHL1 (PGP 9.5): Neuronal biomarker and ubiquitin system protein. Prog. Neurobiol. 90:327-62 (2009).9. Mondello S, et al. Clinical utility of serum levels of ubiquitin C-terminal hydrolase as a biomarker for severe traumatic brain injury. Neurosurgery 70:666-75 (2012).
