One gene-two enzymes? A paper in the October 18 Cell presents a novel, curious twist to already growing evidence that degradation of proteins in the proteasome is a critical line of defense against neurodegenerative diseases. Yichin Liu, working with Peter Lansbury and colleagues of Harvard Medical School in Cambridge, Massachusetts, discovered that a degradation-related enzyme appears to perform a second, different but related, activity that they suggest may be the real pathogenic culprit.

The enzyme, ubiquitin C-terminal hydrolase (UCH-L1) is one of the three genes identified to date to cause familial forms of Parkinson's. (The other two are α-synuclein, thought to become toxic when accumulating in the neuron, and parkin, which is an E3 ubiquitin ligase.) Yet there is a twist to the genetics, too: a UCH-L polymorphism known to protect against PD appears to do so because it encodes a protein that performs less of the second, pathological activity.

The function in humans of UCH-L1 is unknown. In vitro, it recycles ubiquitin. It clips degraded peptides off of ubiquitin coming out of the proteasome, thus freeing it up for the tagging of further waste proteins. A point mutation found in siblings of an affected family (I93M) (Leroy et al., 1998) decreases this in-vitro hydrolase activity of UCH-L1. But this alone could not explain the pattern of disease in the family because the father, who likely carried this autosomal-dominant mutation, had not developed PD. Something else had to be going on. The mystery deepened with the discovery of a polymorphism of the UCH-L1 gene, S18Y. It protects against PD, and yet apparently does not do so by simply increasing the enzyme's known hydrolase activity (see, for example Maraganore et al., 1999; Satoh & Kuroda, 2001.)

In the course of analyzing, in cell culture and cell-free systems, the enzymatic properties of the high-risk and low-risk versions of the S18Y polymorphism, Liu et al. discovered the newly reported enzyme activity. UCH-L1 dimerizes; in this form, it acts as a ligase that adds further ubiquitin molecules to existing α-synuclein-ubiquitin substrates. That directly opposes the hydrolase function. The ligase does its trick with an unusual mechanism that-unlike physiological ubiquitin tagging-does not require ATP, the authors report. UCH-L1 dimerizes with increasing concentrations; UCH-L1 with the pathogenic I93M mutation and wildtype enzymes produced dimer comparable to each other but much more than the S18Y version.

The authors could not show a mechanism of how this UCH-L1 ligase activity might be pathogenic. They propose that it could perhaps inhibit the normal degradation of α-synuclein and thus increase its cytoplasmic concentration to a level where it becomes toxic.

How could this have played out in the father? Complete genotype information on him and the affected siblings was unavailable. Based on further in-vitro tests reported here, Liu et al. speculate that he may have inherited one copy of the S18Y polymorphism along with the I93M mutation, and that the polymorphism moderated the I93M effect by reducing its ligase activity.

By showing that UCH-L1 simultaneously performs a beneficial and a possibly pathogenic enzyme activity, the paper is shaking up the traditional one gene-one enzyme model. Besides adding another dimension to consider in analyzing disease-associated mutations, this study, if confirmed, also subtly changes the rationale for UCH-L1 as a drug target. Ideally, the authors suggest, a drug should interfere with UCH-L1 dimerization since this would promote hydrolase activity at the expense of ligase activity.—Gabrielle Strobel

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Comments on News and Primary Papers

  1. This provides a new insight in protein-degradation study as wellas Parkinson's Disease. It is more interesting how the varations of UCH-L1 affect both activities.

    View all comments by Hiroshi Mori
  2. A very interesting paper: I caution still, however, that a genetic role for UCH-L1 in Parkinson's is not yet established.

    View all comments by John Hardy

References

External Citations

  1. Leroy et al., 1998
  2. Satoh & Kuroda, 2001

Further Reading

Primary Papers

  1. . The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility. Cell. 2002 Oct 18;111(2):209-18. PubMed.