When Protein Breakdown Breaks Down: Bacterial toxin yields signs of Parkinson’s

Certain compounds that hinder cells from destroying waste proteins can produce symptoms of Parkinson’s disease in rats, researchers report. That finding could lead to a new animal model for studying the brain disorder. It also raises the possibility that environmental exposure to a class of compounds known as proteasome inhibitors explains some cases of Parkinson’s in people.

In Parkinson’s disease, neurons die in certain brain areas and abnormal proteins form clusters in other neurons there. Tremors, rigidity, sluggish movement, and balance problems mark the progressive ailment.

The majority of Parkinson’s cases have no known cause, but some cases have been linked to genetic abnormalities that impair cells’ capacity to break down proteins. Barrel-shaped structures known as proteasomes are part of the cellular machinery that normally disposes of molecular trash.

Some chemicals interfere with proteasome activity. These include toxins produced by bacteria and fungi, certain plant compounds, some pesticides, and a synthetic chemical used to treat leukemia. Kevin McNaught of Mount Sinai School of Medicine in New York City and his colleagues have tested whether such inhibitors could produce effects similar to those caused by genetic proteasome abnormalities.

Over 2 weeks, the researchers gave each rat six injections containing the proteasome-inhibiting bacterial toxin epoxomicin, a synthetic proteasome inhibitor called PSI, or a solution devoid of inhibitors. They then studied the animals for up to 21 weeks before dissecting their brains.

Within three to 4 weeks, each rat that had received either of the proteasome inhibitors developed Parkinson’s-like behaviors such as tremors and slowed movement, McNaught and his colleagues report in the July Annals of Neurology. The symptoms worsened with time. Brain tissue from these animals revealed protein clusters in Parkinson’s-related areas of the brain and a reduced number of neurons in those regions. Rats in the third group showed no such changes.

The new findings could provide a “huge clue” to the causes of currently unexplained cases of the disease, says C. Warren Olanow, McNaught’s Mount Sinai colleague. Giving proteasome inhibitors to rats “more closely [simulates] Parkinson’s disease than any animal model that has been developed to date,” he adds.

For that reason and because proteasome inhibitors are relatively easy to handle in the lab, the findings could be a boon for Parkinson’s research, says Valina Dawson of the Johns Hopkins Medical Institutions in Baltimore.

“It’s a great step forward,” says Mark Cookson of the National Institutes of Health in Bethesda, Md. But he adds that the rats’ tremors, as they appear in a brief video that he has viewed, seem somewhat different from those observable in Parkinson’s patients.

“To me, those rats looked miserably sick, but not Parkinsonian,” says neuroscientist Serge Przedborski of Columbia University, who also saw the video. He considers it premature to attribute the rats’ behavioral changes to proteasome inhibition rather than other toxic effects of PSI and epoxomicin.

Nevertheless, McNaught and his colleagues speculate that because proteasome inhibitors occur widely, exposure to these agents could represent an important environmental risk factor for Parkinson’s disease. As yet, human exposure to these compounds remains largely undocumented.