A protein found naturally in the brain may protect against Parkinson's disease (PD), a new study shows. The findings also may lead to an improved understanding of a disorder called early-onset torsion dystonia.
In the study, researchers led by Guy Caldwell, Ph.D., and his wife Kim Caldwell, Ph.D., of The University of Alabama, focused on a protein called torsinA. This protein is defective in people with early-onset torsion dystonia. TorsinA is found naturally in the dopamine neurons that are lost in PD, and it is a component of Lewy bodies - bubble-like compartments of clumped-together proteins that are often found within neurons in PD.
The researchers studied torsinA in tiny worms known as C. elegans. These worms are transparent, live only a few weeks, and contain just eight dopamine neurons, making it easy to see how different factors affect the neurons during the worms' lifespans. The researchers exposed some of the worms to a toxin called 6-hydroxydopamine (6-OHDA). In normal worms, exposure to 6-OHDA causes degeneration and death of dopamine neurons. However, in worms with more than the normal amount of torsin protein (either human torsinA or the worm version, called TOR-2), very few dopamine neurons died. The work was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appeared in the April 13, 2005, issue of The Journal of Neuroscience.*
Torsin showed similar protective ability in worms genetically engineered to overproduce alpha-synuclein protein. An oversupply of alpha-synuclein has been shown to cause PD in humans. Worms with alpha-synuclein alone lost many dopamine neurons as they aged, but those that also had extra torsinA or TOR-2 lost comparatively few neurons. The investigators found that torsin proteins protect against 6-OHDA in a different way than they protect against alpha-synuclein.
Torsin decreases the number of dopamine transporter (DAT) molecules on the surface of neurons, the study showed. DAT molecules allow dopamine to enter the cells. "Part of torsin's role may be to regulate the influx of dopamine into neurons," says Dr. Guy Caldwell. "One of the reasons dopamine neurons die in Parkinson's disease is that dopamine itself can undergo reactive oxidation." Reactive oxidation is a biochemical process in which highly unstable molecules react with and damage components of the cell, such as membranes, proteins, and DNA. Reducing the amount of dopamine that enters the neurons may help protect them against this type of damage.
TorsinA's ability to protect against excess alpha-synuclein did not depend on dopamine transporters, the researchers found. However, the results suggested that dopamine or the dopamine transporter may interact with alpha-synuclein to increase the amount of neurodegeneration in dopamine neurons. TorsinA's ability to protect against alpha-synuclein also might be related to its role in protecting cells from misfolded proteins. Prior studies have shown that torsins function as "molecular chaperones" that help guide the proper folding of proteins, including alpha-synuclein, in cells. "Cells contain many molecular chaperones. It is interesting that torsinA is a chaperone molecule that, when defective, causes a human movement disorder," says Dr. Caldwell. "This points to the importance of these proteins in our brain cells."
It might be possible to increase torsinA's activity using drugs or genetic engineering to provide greater protection against disease, Dr. Caldwell says. Also, humans have multiple torsin genes, and the other torsins might have effects that are similar to torsinA or TOR-2, he adds.
The findings suggest that subtle defects in torsin genes,or factors that influence them, might play a role in susceptibility to PD, Dr. Caldwell says. However, such a link has never been identified.
The researchers are now collaborating with the Stanford Human Genome Center, The Parkinson's Institute, and the Mayo Clinic on studies to identify other proteins or small molecules that might prevent dopamine neurons from dying. They also are using worms to identify other genes and chemical compounds that influence torsin activity. The findings may lead to new treatments for PD and some forms of dystonia.
While the results of this study appear promising, much more work needs to be done before researchers could test torsins or torsin-enhancing drugs as treatments for human disease. "This work suggests that higher amounts of torsin would protect neurons, but we would need to make sure there aren't negative consequences," says Dr. Caldwell. "While the findings in worms are a wonderful starting point, use of other animal models would be necessary before we could extrapolate these findings for therapeutic use."
The NINDS is a component of the National Institutes of Health within the Department of Health and Human Services and is the nation’s primary supporter of biomedical research on the brain and nervous system.
*Cao S, Gelwix CG, Caldwell KA, Caldwell GA. "Torsin-mediated protection from cellular stress in the dopaminergic neurons of Caenorhabditis elegans." The Journal of Neuroscience, April 13, 2005, Vol. 25, No. 15, pp. 3801-3812.