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In a rare, inherited form of Parkinson's disease, the disease develops because an enzyme called parkin is mutated and fails to tag other proteins destined for removal from the cell. Researchers speculate that the accumulation of these unknown proteins in the neurons kills the cells.

P&S researchers now report they have discovered the identity of the previously unknown neuron-killing proteins. The researchers—Dr. Asa Abeliovich, assistant professor of neurology and pathology, and his graduate student John Staropoli—also found that they could save neurons from dying from a Parkinson's-like process by using parkin to prevent accumulation of the protein. Because parkin may also be important in the more common, sporadic form of Parkinson's, the findings may be used to develop a therapy for all Parkinson's patients. The research was published in the March 6 Neuron.

Parkin was first discovered in 1998 by a Japanese research group and is one of three proteins that have been linked to inherited forms of Parkinson's. Normal parkin appears to help tag certain proteins with ubiquitin molecules. A protein covered with ubiquitin molecules tells the cell that the protein should be discarded.

But which proteins parkin tags was unclear. The researchers began looking for parkin's substrate by identifying other proteins that attach to parkin inside the cell. They found several other proteins, but none of them turned out to be tagged by parkin. Instead, the proteins form a complex with parkin that helps the enzyme add ubiquitins to the still-unknown substrate.

One of the proteins in the complex, hSel-10, then led the researchers to parkin's real target: cyclin E. They found that normal parkin ubiquinates cyclin E, causing its degradation, but that mutated parkin from patients with the inherited disease is unable to ubiquinate the target.

Cyclin E is an intriguing molecule because it accumulates in neurons that are dying from excitotoxicity, a process of overstimulation thought to occur in sporadic Parkinson's disease. It became even more intriguing when the researchers found excess cyclin E in the dopamine neurons of a few patients with sporadic disease as well as a few patients with inherited disease.

The presence of cyclin E in the neurons led the researchers to speculate that preventing cyclin E accumulation could prevent neurons from dying from excitotoxicity, and possibly Parkinson's disease. The researchers tested parkin's effect on cell death after cells had been exposed to an excitotoxic molecule called kainate.

In dopamine neurons taken from mice, the researchers found that excess parkin in the overstimulated cells reduced cyclin E and prevented cell death. Depleting the neurons of parkin had the expected effect of increasing cell death, but only in cells exposed to kainate. Parkin deficiency did not lead to neuron death until they were stressed by overstimulation.

The next step, the researchers say, is to see if parkin can also save neurons in the brain. "We want to see if the results hold up in animal models," Dr. Abeliovich says. "And we want to identify more of the players to get a better grasp of why parkin is protective."

Mr. Staropoli says parkin may have other substrates, but that another important protein associated with Parkinson's disease is probably not one of them. Initial reports indicated alpha-synuclein—the protein inside the Lewy Bodies that are scattered through the dopamine neurons in sporadic Parkinson's patients—was a parkin target. But Dr. Abeliovich's lab and other groups have not been able to repeat the finding.

Nevertheless, the researchers say parkin may be involved in sporadic Parkinson's disease, as suggested by their finding that cyclin E accumulates in the dopamine neurons of patients with sporadic disease. "There may be ways to inhibit cyclin E accumulation if cyclin E turns out to be important," Mr. Staropoli says, "but the bottom line is we need to know more about the dopamine neurons in disease before we can intervene therapeutically."

The research was funded by the Henry and Marilyn Taub Foundation, the Rockefeller Brothers Foundation, and St. Jude Children's Research Hospital. John Staropoli is a M.D./Ph.D. student in the Integrated Program in Cellular and Molecular Biology.


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