NEW RESEARCH SHEDS LIGHT ON PARKINSON'S CAUSES
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NEW RESEARCH SHEDS LIGHT ON PARKINSON'S CAUSES.
ORLANDO, Sunday, Nov. 3 - Researchers in Baltimore are investigating protein-protein interactions as important causal factors in Parkinson's disease. Meanwhile, other scientists have developed fruit flies as animal models of Parkinson's while others are using rodents dosed with pesticides to investigate links between environmental influences and the development of this chronic, progressive neurological disorder.
The physical symptoms that characterize Parkinson's disease - limb tremor, slow movement or an inability to move, a shuffling gait, impaired speech or impaired swallowing - result from a decrease in production of the neurotransmitter dopamine. The death or impairment of nerve cells (neurons) in an area of the brain called the substantia nigra leads to the decrease of this chemical messenger. New research was presented today during the 32nd annual meeting of the Society for Neuroscience.
Parkinson's disease affects as many as one million Americans, most of them middle-aged and elderly (but some 10 percent of those affected are younger than 40, according to the American Association of Neurological Surgeons). The disease strikes people as diverse as actor Michael J. Fox, boxer Muhammed Ali, former U.S. Attorney General Janet Reno and Pope John Paul II.
Although genetics does not seem to play a major role in Parkinson's disease, clues from the two main inherited forms of the disease may provide new key information related to the development of the more common non-inherited forms.
Mutations in two different proteins - parkin or alpha-synuclein - characterize the inherited forms of Parkinson's, says Ted Dawson, MD, PhD, of The Johns Hopkins University School of Medicine in Baltimore. "What we've seen in our lab is that under normal circumstances each of these proteins interacts with another protein called synphilin. But the mutations disturb this interaction."
Many of the dead and dying nerve cells in brains touched by Parkinson's have protein blobs called Lewy bodies that contain parkin, alpha-synuclein and synphilin. Dawson's research suggests that parkin plays an important role in regulating the other proteins in the Lewy bodies and that synphilin acts as an intermediary between parkin and alpha-synuclein. In fact, Dawson says, Lewy bodies do not form in the absence of parkin.
Parkin also recruits another protein, ubiquitin, whose function is to tag other proteins for destruction. The familial associated mutations in parkin interfere with ubiquitin-tagging, which leads to the accumulation proteins such as synuclein and synphilin, says Dawson.
"When parkin interacts with and ubiquinates synphilin, the result is the formation of Lewy bodies," he explains. "We suspect that ubiquitin and protein mishandling might be very important in Parkinson's disease, that perhaps the altered destruction of alpha-synuclein and other targets of parkin, such as synphilin, could be the common thread in the various forms of Parkinson's disease.
One of Dawson's colleagues has created a transgenic mouse that overproduces human synuclein. "This is one of the first realistic animal models for this disease," says Dawson. "The older 1,2,3,6-tetrahydropyridine (MPTP) model is one of the best animal models for Parkinson's but some people don't think it's realistic because it is an acute model. But our synuclein model might be considered more realistic because the mice develop a chronic, age-dependent neurodegeneration in much the same way that humans develop Parkinson's disease."
Another animal model, the lowly fruit fly, also may prove to be a useful ally in the search for new knowledge about and drugs to combat Parkinson's disease.
Mel B. Feany, MD, PhD, of Harvard Medical School and Brigham and Women's Hospital in Boston, and her colleagues, have genetically engineered fruit flies to develop symptoms of Parkinson's.
"These flies have the human gene that codes for the protein alpha-synuclein and, just like humans, these flies lose the ability to move properly as they age," she explains. "When you put normal fruit flies into a plastic vial, they like to walk up the sides and onto the top. Middle-aged flies that have the human gene spliced into their DNA cannot do this like genetically normal fruit flies. They can't hang on to the sides, and just fall to the bottom."
The flies experience the deaths of dopamine-producing neurons in their brains. The brains of these flies also contain fibrous bundles of alpha-synuclein that resemble Lewy bodies.
"Fruit flies have many strengths as animal models of disease," Feany says. "They are inexpensive and their life spans are extremely short, making them ideal as multi-generational subjects. Furthermore, they share many genes with higher organisms, including humans."
Feany also is using these transgenic flies to test selected candidate drugs for their effects on neurodegeneration and Lewy body formation.
Other animal models are helping researchers piece together other parts of the Parkinson's disease puzzle. One rodent model was developed in the early 1980s after it became known that some heroin addicts developed symptoms of Parkinson's disease after injecting themselves with a drug preparation contaminated by 1,2,3,6-tetrahydropyradine (MPTP). MPTP changes in biologic systems to MPP+, which inhibits an enzyme in mitochondria, the intracellular organelles that provide cells with energy. This enzyme is known as complex I.
Several pesticides also inhibit complex I. So, J. Timothy Greenamyre, MD, PhD, of Emory University in Atlanta, and his colleagues hypothesized that treatment with low levels of the pesticide rotenone might induce Parkinson's in rodents.
The scientists administered rotenone to rats over a period of several weeks. "When we examined their brains, we saw anatomical and biochemical changes virtually identical to those seen in Parkinson's disease," he says.
These results, he adds, suggest that environmental factors, possibly including pesticides, may be involved in the development of some human cases of Parkinson's disease. Although this research does not prove that rotenone causes Parkinson's in humans, it lends credence to the concept that environmental toxins - even those considered relatively benign - may contribute to the development of the disease.
Greenamyre now is conducting additional research to find answers to additional questions. "What is the exact mechanism by which rotenone and, possibly, other environmental toxins, kill the neurons involved in Parkinson's disease?" he asks. "Specifically, what other pesticides or chemicals are capable of causing neurodegeneration and parkinsonism?"
Another aspect of research, he says, involves testing drugs that may slow or stop the neurodegeneration that occurs in Parkinson's disease. "If we learn more about the mechanism by which rotenone causes these symptoms and effects, it may be possible to devise therapies to block toxicity. This should translate into treatments that could slow or halt progress of the disease at its earliest stages."
