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NEUROLOGY
Enzyme Linked to Pathology of Parkinson's Disease Appears Two-faced
An enzyme implicated in Parkinson's disease performs two opposing actions related to protein degradation, according to a study in the Oct. 18
Cell. The laboratory of Peter Lansbury found that the enzyme, UCH-L1, exhibits an activity in vitro that counteracts its previously known function.
From left to right, Peter Lansbury, Yichin Liu, Hilal Lashuel, and Zhihua Liu uncovered a dual role for UCH-L1 that explains why a genetic variant of the enzyme may be protective against Parkinson's disease. (Photo by Graham Ramsay)
Much research has focused on how the aggregated proteins found in neurodegenerative diseases like Parkinson's are produced, overproduced, folded, and eventually clumped together. But a defect in protein degradation could also lead to a pathogenic traffic jam in the cell. Normally, strings of ubiquitin molecules are attached to proteins to signal which ones will get canned--chewed up into amino acids by the proteasome and recycled for later use. UCH-L1's function in humans is not known, but in vitro studies suggested it helps cut the ubiquitin strings from the small peptides that the proteasome spits out so they can be broken down into amino acids.
But the team found that, in vitro, UCH-L1 actually elongates ubiquitin strings on alpha-synuclein, the protein that accumulates in neurons of Parkinson's patients. Lansbury's team believes it has found an answer to this puzzle: UCH-L1 has the ability to both unravel ubiquitin strings and knit them together.
The finding may help explain the relationship between UCH-L1 and familial Parkinson's. Studies of populations of Parkinson's patients vs. controls have shown that a common polymorphism the gene that encodes UCH-L1 is associated with decreased likelihood of acquiring Parkinson's. Lansbury's team, led by research fellow Yichin Liu, found that the protective variant of UCH-L1 had a reduced ability to link ubiquitin molecules together. It may be this ubiquitin knitting that is pathogenic, by clogging up the degradation pathway. The team found that the wild type version of the protein has a tendency to stick together in pairs, and they believe this molecular pairing acts as a switch between one activity and the other.
--Courtney Humphries
Copyright 2002 by the President and Fellows of Harvard College
