Jumbo Gene Offers Clue to Parkinson's

Scientists have discovered a massive gene that, when mutated, causes a rare condition similar to Parkinson's disease. Although the finding--reported in tomorrow's issue of Nature--won't resolve a long-running debate over whether a genetic flaw or some environmental insult is the primary culprit behind most Parkinson's cases, neurobiologists hope that it will offer a glimpse at the shadowy players involved in the molecular wreckage of a patient's brain.

To hunt down the new gene, a team led by Nobuyoshi Shimizu of Keio University School of Medicine, and Yoshikuni Mizuno of Juntendo University School of Medicine, both in Tokyo, focused on a small group of Japanese families afflicted with a rare disease called autosomal recessive juvenile parkinsonism (AR-JP), the symptoms of which sometimes start developing in teenagers. In contrast, people with common nonhereditary Parkinson's show symptoms after age 40. Knowing that the AR-JP gene lay somewhere on chromosome 6, the researchers used positional cloning--a technique in which ever-finer maps of inherited mutations narrow a gene's possible location--to nab the gene, which they've dubbed parkin.

The team soon discovered that the Parkin protein is "one of the most unique proteins ever known," says Shimizu. One portion resembles ubiquitin, a protein that, like Charon--the mythical boatman of the river Styx--ferries defective or spent proteins to proteosomes that chop them up. Defects in Parkin's ubiquitin-like section may subvert protein degradation and lead to toxic protein buildup. Parkin also has a zinc finger, a motif often found in proteins that help regulate gene expression.

"This research is very important," says Robert Nussbaum of the National Human Genome Research Institute in Bethesda, Maryland, "because we'll want to see if a deficiency of Parkin might be occurring in nonhereditary Parkinson's disease as well," perhaps as a secondary effect of underlying disease processes. Indeed, says Shimizu, in nonhereditary Parkinson's, "some environmental factor may be altering the form of Parkin over time."