Genetic Research Yields Controversial Parkinsons Drug Target

January 5, 2006

Pharmaceutical Executive

Pharmaceutical Executive, Pharmaceutical Executive-01-05-2006, Volume 0, Issue 0

Two experts are split over the importance of research on a gene linked with a rare genetic type of Parkinson’s disease. One thinks it could hold the key to new treatment. The other thinks it is too rare to be relevant.

Research on a gene linked with a rare type of Parkinson’s disease could lead to a new drug target, scientists at the University of Colorado believe.

    Although most people who develop Parkinson’s have environmental, not genetic, versions of the disease, several genes have been associated with its incidence, explained Curt Freed, professor of clinical pharmacology and toxicology at the University of Colorado Health Sciences Center.

    Freed co-authored a paper about one such gene, DJ-1. His research showed that cells engineered to produce more than the normal amount of DJ-1 showed improved hardiness in the face of two types of stress that scientists believe are associated with Parkinson’s.

    Parkinson’s occurs with the death of brain cells that produce dopamine, a brain chemical that interacts with nerve cells that determine muscle movement, Freed said. This leaves patients with very low levels of this important neurotransmitter.

    Usually the cause of Parkinson’s is unknown, Freed explained, but one suspected cause is stress from exposure to harsh chemicals that oxidize the cellular environment. Dopamine-producing neurons are particularly sensitive to chemical stress, he said.

    When Freed and his colleague, Wenbo Zhou, exposed neurons that over-expressed DJ-1 to hydrogen peroxide, an oxidizer that kills dopamine cells in culture, their survival rate improved. When they exposed similar cells with no DJ-1 to hydrogen peroxide, a lower-than-normal number of cells survived. According to Freed, DJ-1 responded to the stress by turning on a gene that produced an anti-oxidant, glutathione.

    One sign of Parkinson’s disease is the presence of built-up protein deposits called Lewy bodies in the neurons, Freed said. These disruptive structures contain the protein alpha-synuclein. Mutations in the gene for alpha-synuclein are associated with genetic Parkinson’s disease.

    Freed and Zhou created cells with a mutation in the alpha-synuclein gene that cause the protein to aggregate and have toxic effects. Engineering these cells to over-express DJ-1 improved survival. When the mutant alpha-synuclein cells had no DJ-1, they were less viable than usual.

    When exposed to deposits of alpha-synuclein, DJ-1 activated an enzyme known to inhibit clumping, heat shock protein 70 (Hsp70).

    According to Freed, these findings make DJ-1 a good candidate for drug development. He and his colleagues are investigating two avenues for using DJ-1 to treat Parkinson’s.

    The first involves using gene therapy to insert the over-expressing DJ-1 gene into dopamine neurons. In theory, this could increase the presence of DJ-1 enough to protect the cells from oxidation and protein aggregation.        

    But Freed admits that gene therapy is challenging.

   He also imagines discovering a compound that turns on DJ-1 and triggers protective effects without damaging the cells.

    Even so, Freed acknowledged that even if either of these methods were successful in increasing the amount of DJ-1 present in a dopamine neuron, this would not necessarily prevent Parkinson’s symptoms.

    Demetrius Maraganore, a professor of neurology at the Mayo Clinic in Rochester, doubts that DJ-1 is the answer.

    A mutation in the DJ-1 gene is such a rare cause of Parkinson’s disease that Maraganore finds it unlikely that the protein could lead to a new treatment. He even thinks it is possible that the mutation causes a similar disease that is not actually Parkinson’s.

    “I have some cynicism as to whether that particular gene, or its encoded protein, are the best target for research, let alone new therapies,” he said.

    His statements are based on research that he and other Mayo scientists conducted on all of the genes associated with Parkinson’s. Certain mutations in these genes can cause rare forms of the disease, he said. If the mutation happens, an individual will get Parkinson’s. The Parkinson’s associated with DJ-1 falls into this category.

    But common variations throughout the population of some genes that Maraganore studied could influence an individual’s risk of developing Parkinson’s, he said. For example, certain variations of the alpha-synuclein gene could increase the likelihood of Parkinson’s symptoms, depending on environmental factors.

    In Maraganore’s research, the common variants of the DJ-1 gene were not associated with increased risks.

    He added, however, that even if he is right and DJ-1 is not central to the disease, studying the gene has some merits for general knowledge about Parkinson’s.