Deadly Giveaway
Authors: Davenport R. John 
Published: August 2003

A protein that snatches life from neurons does so by what it gives, not by what it takes away, according to new research. It wastes a molecule intended to destroy a toxic protein and ultimately promotes Parkinson's disease (PD), according to new research. The discovery could solve the mystery of why a mutation linked to PD doesn't always trigger disease and presents a new candidate target for brain-saving drugs.

PD kills neurons that control muscle movement, perhaps because clumps of a protein called α-synuclein accumulate in doomed cells. A protein called Parkin normally labels α-synuclein with ubiquitin, a tag that sends molecules to the cellular garbage heap. Individuals who carry defects in the
Parkin
gene have an increased risk of developing PD. A mutation in another gene--
UCH-L1
--also promotes PD, according to genetic studies of one family. The UCH-L1 protein normally removes ubiquitin from peptides for recycling, thus making it available to condemn misbehaving proteins. Glitches in that process could allow α-synuclein to persist. Not all perturbations in
UCH-L1
, however, cause trouble; a different mutation confers resistance to PD, although no one knows why.

In the new work, Liu and colleagues compared how the two mutations alter UCH-L1's function. Cultured cells that produce normal or PD-promoting UCH-L1 amassed large amounts of α-synuclein, whereas cells with the PD-preventing version did not. But the normal and PD-preventing UCH-L1 clipped ubiquitin from peptides with similar efficiencies, suggesting that UCH-L1 possesses other capabilities responsible for α-synuclein buildup.
Further tests revealed that normal UCH-L1 also tacks ubiquitin molecules onto α-synuclein. The PD-preventing mutation--but not the PD-promoting one--thwarts this capability. The extra ubiquitin, however, doesn't stimulate α-synuclein's destruction. As a result, UCH-L1 could deplete ubiquitin from the available pool and ultimately reduce α-synuclein demolition--but by sticking ubiquitin onto α-synuclein, instead of by leaving it on protein fragments as previously thought.
Additional experiments suggest that the ubiquitin-adding activity depends on UCH-L1's ability to pair up and that the PD-preventing alteration keeps UCH-L1 molecules apart. The PD-preventing mutation offsets the PD-promoting one, at least in a test tube. An equal mixture of PD-promoting and -preventing UCH-L1 was considerably poorer at attaching ubiquitin to α-synuclein than was a mixture of the PD-promoting UCH-L1 and the normal protein. In the single family whose members carry the harmful UCH-L1 mutation, a father of two affected individuals carries the mutation and does not have PD. The authors propose that the PD-preventing UCH-L1 mutation--which occurs commonly--could protect him and others from the disease, although human data aren't yet available to support the idea.
"It's an exciting new paper," says biochemist Keith Wilkinson of Emory University in Atlanta. The work suggests that small molecules that disrupt ubiquitin tagging by UCH-L1 could reduce the risk of developing PD, he says. Neuroscientist Ted Dawson of Johns Hopkins University in Baltimore says that researchers will need to prove that UCH-L1 can add ubiquitin in intact animals. But if the finding pans out, it could have implications beyond PD, Wilkinson adds: The PD-preventing mutation also seems to delay the onset of Huntington's disease. Mimicking the alteration could foil multiple degenerative diseases that involve buildup of sticky proteins, a gift anyone would welcome.
--R. John Davenport

Y. Liu, L. Fallon, H. A. Lashuel, Z. Liu, P. T. Lansbury, The UCH-L1 gene encodes two opposing enzymatic activities that affect α-synuclein degradation and Parkinson's disease susceptibility.
Cell
111
, 209-218 (2002).
[Abstract]
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