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Sentry Enzyme Blocks Two Paths to Parkinson’s Diseas

ted with this drug, the presence of GST pi in the dopaminergic neurons prevented activation of cJUN, a molecule that triggers apoptosis. These findings are evidence that GST pi prevents apoptosis in dopaminergic neurons of the substantia nigra, Smeyne said.

The investigators also showed in cell culture studies that blocking production of GST pi in substantia nigra cells left them vulnerable to MPTP, causing a significant death rate among these cells. In addition, when the investigators blocked GST pi production in the dopaminergic neurons of the substantia nigra, about one-quarter of them died, even though they were not treated with MPTP. “This suggests that even in the absence of MPTP the enzyme GST pi plays a critical role in preventing cell death that may occur with the natural buildup of free radicals,” Smeyne said.

Finally, the investigators studied the effect of MPTP on the substantia nigra of normal, “wild-type” mice and mice that lacked one (+/-) or both (-/-) genes for GST pi. Wild-type and GST pi (+/-) mice showed similar resistance to MPTP, but GST pi (-/-) mice lost slightly less than half of their dopaminergic neurons following treatment with MPTP. Six hours after MPTP treatment, the formation of free radicals increased 300 percent in the substantia nigra of GST pi (-/-) mice compared with the substantia nigra of GST pi (+/+) mice. These results are additional evidence that GST pi may play an important role in preventing Parkinson’s disease,” Smeyne said.

Results of the St. Jude study showing the importance of GST pi could help to explain previous work by other researchers linking loss of this enzyme to destruction of dopaminergic neurons. For example, there is some evidence that alterations in the gene for GSP pi are linked to increased risk of Parkinson’s disease after pesticide exposure. Also, although most Parkinson’s disease cases have no known cause, experts believe that they are caused by the interaction of
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