UCHL1 (PGP 9.5): neuronal biomarker and ubiquitin system protein.

UCHL1/PGP 9.5 (also known as UCHL1 and PGP 9.5) was first detected as a "brain-specific protein" over 28 years ago. The protein is highly conserved and localized in neurones and neuroendocrine cells in vertebrates, forming an estimated 5-10% of cytoplasmic protein. A minor proportion in brain is tightly membrane-bound and the protein is also found in human oocytes and spermatogonia. A few specialised neurones lack UCHL1/PGP 9.5 and possibly replaceable neurones have low levels of the protein. UCHL1/PGP 9.5 shows sequence homology with UCHL3 (ubiquitin carboxyl-terminal hydrolase L3) and will similarly hydrolyse C-terminal adducts of ubiquitin. Both proteins show an unusual highly knotted structure with five "crossovers" but there are differences in substrate specificity, amino-acid sequence, and tissue distribution between them. There is no convincing evidence that UCHL1/PGP 9.5 can remove ubiquitin from proteins destined for proteasomal degradation, rather the substrate(s) of the enzyme appear to be one or more as yet unidentified short ubiquitin C-terminal extensions. Other suggested functions of the protein are plausible but largely unconfirmed. Isolated loss of UCHL1/PGP 9.5 function seen in the gracile axonal dystrophy (GAD) mouse due to a deletion in its gene results in a failure of axonal transport and a "dying-back" axonopathy beginning distally in long axons. The evidence that mutations in the UCHL1/PGP 9.5 gene lead to either significant susceptibility to or protection from Parkinson's disease (or other human neurodegenerative disorders) is weak. Antibodies to the protein have found remarkably widespread application in the detection of fine nerves in peripheral tissues of many vertebrate species.