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Embryonic Stem Cells Yield Parkinson's Clue
Researchers use cells to gain insight into gene function

Proponents of embryonic stem cells usually emphasize their therapeutic potential, but now for the first time, CUMC researchers have used embryonic stem cells to make an important scientific discovery.

Using embryonic stem cells from mice, Asa Abeliovich, M.D., Ph.D, assistant professor of neurology and pathology, and his colleagues uncovered how a gene known to cause Parkinson's disease leads to the death of neurons. It's the first time that oxidative stress, a process previously thought to be a primary instigator of neuron death, has been tied to a genetic mutation. The research appears in two papers in the November issue of PLoS Biology.

"It really underscores the importance of the correlation between oxidative stress and the disease that we see in patients, but until now, we didn't have a mechanism to explain it," says Dr. Abeliovich. During oxidative stress, oxygenated molecules that can damage and ultimately kill the neuron accumulate in the cell.

Parkinson's is a progressive disease caused by the death of dopamine neurons in one area of the brain, but in most cases scientists don't know what sets off the degeneration.

In rare instances, the disease can be traced to mutations in one of four different genes. Parkinson's researchers believe that learning what these genes do and how they interact will also point them to the cause of most cases of the disease.

Dr. Abeliovich and his colleagues wanted to know what one of these genes, DJ-1, does in the cell and how it leads to Parkinson's when mutated.

They turned to mouse embryonic stem cells to answer these questions because of technical difficulties with other cell sources.

"This is a different use of stem cells than most people envision," Dr. Abeliovich says. "There's lots of excitement in using embryonic stem cells to generate neurons for replacement therapies, but the cells are also valuable for mimicking the neurons that die in patients with Parkinson's."

In the new study, Cecile Martinat, Ph.D., a postdoctoral researcher in Dr. Abeliovich's lab, devised a way to insert a mutant DJ-1 gene into embryonic stem cells. The researchers then coaxed the cells into dopamine neurons before putting the cells under oxidative stress. DJ-1, the researchers found, protects the cell from oxidative stress by repairing the oxygenated proteins before they can go on to kill the cell.

In the second paper, Shoshana Shendelman, a student in the Graduate School of Arts and Sciences, looked for more details about this mechanism and found a tantalizing link between DJ-1 and another Parkinson's gene called alpha-synuclein.

Alpha-synuclein proteins are believed to be key to finding the cause of the disease – even though the alpha-synuclein gene is mutated in only a few patients – because the proteins clump together in the dopamine neurons of almost all Parkinson's cases. The new research suggests DJ-1 may stop alpha-synuclein from clumping.

Further success in piecing together the Parkinson's puzzle may depend on extending the new method to human stem cells. "Our research opens up the idea of using human embryonic stem cells for research, which would give us a unique opportunity to work with human neurons," Dr. Abeliovich adds. "We've learned a lot with mice, but mice and humans are different, in obvious and nonobvious ways."

The research was supported by the NIH, the American Parkinson's Disease Association, and the Spitzer, Taub, Rockefeller Brothers, and MJ Fox Foundations.

—Susan Conova