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Although the cause of Parkinson's disease is unknown, scientists recently have shown that genetic alterations, such as mutations in the parkin or synuclein genes, and environmental insults, such as exposure to pesticides or other agents, independently can increase susceptibility to the disease.

Now, findings from research led by Dr. William Dauer, assistant professor of neurology and pharmacology, demonstrate genetic and environmental factors may employ a common molecular pathway that uses the protein synuclein to spur pathology.

The results, which were published in the Oct. 29 issue of the Proceedings of the National Academy of Sciences, advance understanding of the genetic and environmental interplay in Parkinson's. The findings also add credence to a current theory that Parkinson's could result from an environmental assault working in a permissive genetic background.

Idiopathic Parkinson's disease affects approximately 1 million Americans, with symptoms usually appearing when a patient is older than 50. The disease affects neurons that manufacture the neurotransmitter dopamine and causes their destruction. When a significant amount of these dopaminergic neurons die, patients start exhibiting the tremor, muscle rigidity, and movement problems characteristic of the disease.

For some time, researchers have debated the relative role of genes and the environment in causing the disorder. During most of the 20th century, researchers believed environmental factors played a key part because of evidence available. In the early part of the century, victims of viral encephalitis, as portrayed in the book and movie "Awakenings," later developed Parkinson's-like symptoms and benefited from dopamine replacement treatments.

In the late 1980s, researchers also found that a substance, called MPTP, could lead to Parkinson's-like symptoms. At the time, some drug users had injected a new synthetic narcotic that included MPTP as a contaminant. Several wound up in the hospital with movement problems similar to Parkinson's. Since then, researchers have used the neurotoxin MPTP to create animal models of Parkinson's to study the disease. Other studies suggested exposure to pesticides may also increase susceptibility to Parkinson's.

"But the problem with the environmental hypothesis is that epidemiological studies have not been able to reveal clusters of disease cases as one would expect from an exposure in the population," according to Dr. Serge Przedborski, professor of neurology and pathology and study co-author.

Within the past 10 years, investigators have identified a few families in which mutations in the synuclein, parkin, and other genes have been linked to the disease. But in most Parkinson's cases, scientists cannot detect mutations in these genes. A hallmark, though, of non-inherited Parkinson's is the presence of Lewy bodies—abnormal aggregates of proteins that include synuclein and parkin—in brains. "These Lewy bodies seem to establish a link between the rare genetic and common forms of the disease," Dr. Dauer says.

"Now, researchers believe an interaction of environmental substances in genetically susceptible individuals may be leading to most cases of the disease," Dr. Przedborski says. In rare patients with mutations, a mutant protein produces dopamine neuron destruction, while in most patients (without clearly inherited disease) an environmental toxin may selectively affect those people with subtle changes in one or more target genes.

"Our findings provide evidence for a possible link between environmental and genetic influences in non-genetic Parkinson's by showing synuclein is a key molecule in MPTP-induced neurodegeneration," Dr. Dauer says.

Initially, Dr. Dauer and his team genetically engineered mice that lacked the alpha-synuclein gene to understand the role of the protein product in causing the disease. Surprisingly, they found mice without the gene seemed to act normally even though alpha-synuclein is highly abundant in nerve terminals.

To explore whether dopamine neurons that lack alpha-synuclein display an altered susceptibility to neurodegeneration, the researchers then exposed the mice to MPTP. While dopamine neurons from normal mice exposed to MPTP developed the expected degeneration, the dopamine neurons in the mice without alpha-synuclein were almost completely resistant to the toxin.

MPTP, as does the pesticide rotenone, acts by binding to a mitochondrial protein and preventing cellular respiration. But in contrast to the MPTP, the researchers found rotenone killed dopaminergic neurons without alpha-synuclein. Because MPTP, unlike rotenone, interacts with synaptic transporters and neurotransmitter vesicles as it enters nerve cells, the researchers believe their findings suggest that alterations in synaptic function in dopaminergic neurons without synuclein prevent MPTP from getting to the mitochondrion to do damage. The results also imply that changes in the normal function of alpha-synuclein may be important to dopamine neuron viability.

Dr. Dauer now is testing whether changes in the function of dopaminergic synapses are responsible for the resistance to MPTP of the cells without synuclein. Additionally, he is studying if Parkinson's disease-causing mutations in alpha-synuclein also alter the resistance of dopamine neurons to MPTP. These studies could help elucidate the normal function of alpha-synuclein and how mutations act to cause neurodegeneration.

The research was funded by the Parkinson's Disease Foundation, the Lowenstein Foundation, and the National Institute of Neurological Diseases and Stroke.


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