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."