Drug Boosts Activity of Anti-Parkinson's Disease Gene

In the current study, which was published in the March 3, 2011, online edition of the Journal of Biological Chemistry, they searched for chemical compounds that could increase DJ-1 activity.

After screening a number of small molecules, they found that the histone deacetylase inhibitor phenylbutyrate increased DJ-1 expression by 300% in the N27 dopamine cell line and rescued cells from oxidative stress and mutant alpha-synuclein toxicity. In mice, phenylbutyrate treatment led to a 260% increase in brain DJ-1 levels and protected dopamine neurons against 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) toxicity. In a transgenic mouse model of diffuse Lewy body disease, long-term administration of phenylbutyrate reduced alpha-synuclein aggregation in brain and prevented age-related deterioration in motor and cognitive function.

"Drugs currently used to treat Parkinson's disease just treat symptoms; they do not stop the disease from getting worse,” said senior author Dr. Curt Freed, professor of medicine and pharmacology at the University of Colorado School of Medicine. "We have now discovered that we can prevent the progression of the disease by turning on a protective gene in the brain”

"We look forward to a future when Parkinson patients will be able to take a pill that will turn on the DJ-1 gene and stop the progressive disability associated with the illness,” said Dr. Freed. "Right now, when you get the diagnosis of Parkinson's, you can expect to have a steady decline in the ability to move. While drugs like L-DOPA are very important for generating dopamine in the brain and making movement possible, these drugs have little impact on the ongoing deterioration of the patients' own brain cells.”

A major drawback of phenylbutyrate is that patients must take very large doses, 16 grams per day or 32 large tablets taken at frequent intervals. For this reason, the investigators continue to seek for other drugs to spur DJ-1 gene activity.

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University of Colorado School of Medicine