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Biological Chemistry

Parkinson's Picture Grows Clearer

Researchers find a protein that impedes protein disposal, examine effect of cutting calories

by Sophie L. Rovner
January 3, 2005 | A version of this story appeared in Volume 83, Issue 1

Lozano (right) and colleague Suneil K. Kalia track down the causes of Parkinson's disease.
Lozano (right) and colleague Suneil K. Kalia track down the causes of Parkinson's disease.

A diagnosis of parkinson's disease leaves little doubt as to the outcome--there is no cure. The neurodegenerative disease causes symptoms including tremor and rigidity that can lead to severe disability. Although it's known that Parkinson's kills neurons that produce dopamine, the details remain murky. Two new reports may help illuminate the mechanism and point the way to potential treatments.

Andres M. Lozano, a senior scientist at the University of Toronto, in Ontario, and several other researchers there and at the University of Ottawa, in Ontario, and McGill University, in Montreal, have identified a protein in rats that interferes with the normal function of the protein parkin [Neuron, 44, 931 (2004)]. Parkin helps cells dispose of unwanted proteins. Some 10% of Parkinson's cases, referred to as familial, are caused by mutations, many in the gene for parkin. The mutated form of parkin is unable to carry out its normal function, and the resulting buildup and aggregation of undesirable proteins destroys the affected neurons.

The parkin-interfering protein, bcl-2-associated athanogene 5 (BAG5), is activated when a dopamine neuron is damaged. It also hampers the function of the chaperone Hsp70, a neuroprotective heat-shock protein that normally prevents the formation of protein aggregates.

As a result of BAG5's interference, the Lozano team reports, parkin clumps into aggregates that resemble Lewy bodies, which are a hallmark of human Parkinson's disease. This aggregation limits parkin's ability to clear neural cells of unwanted proteins. Hence, BAG5 "may serve as a useful therapeutic target," the researchers write.

THE WORK adds support to the hypothesis that a common pathogenic mechanism exists for familial and the more common "sporadic" forms of the disease. As Kenny K. K. Chung and Ted M. Dawson, neuroscientists at Johns Hopkins University School of Medicine, note in a commentary, the Lozano team's work "clearly illustrates the importance of studying genes that are linked to familial Parkinson's disease, as significant advances in the understanding of the pathogenic mechanisms of [the disease] continue to arise from these studies." Meanwhile, at the National Institute on Aging (NIA), Mark P. Mattson, chief of the neurosciences lab, and his colleagues are looking at an entirely different way to battle Parkinson's. They report that restricting the diet of monkeys protects them from an animal model of the disease [Proc. Natl. Acad. Sci. USA, 101, 18171 (2004)]. This finding could be welcome news, as the researchers note that "there is currently no established intervention to prevent, or decrease the risk of, Parkinson's disease."

Together with senior investigator Donald K. Ingram, who has been studying the effects of caloric restriction on aging in monkeys at NIA for nearly 20 years, Mattson tested the hypothesis that caloric restriction would protect rhesus monkeys against Parkinson's disease. In their study, half the monkeys were fed a normal diet, and the rest were fed a diet with 30% fewer calories. After six months, all the monkeys were injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP selectively kills dopamine neurons in the brain's substantia nigra region. Such cell death also occurs in Parkinson's. The animals were maintained on their respective diets and observed for four to five months after treatment with MPTP.

The calorie-restricted monkeys fared better in some measures of neurological fitness. The levels of dopamine and its metabolites in their brains were significantly greater than in the controls. The data show that caloric restriction reduces the dopamine depletion induced by MPTP.

Caloric restriction also affected glial cell-line-derived neurotrophic factor (GDNF), which is known to promote the survival of dopamine neurons. The calorie-restricted monkeys had three times as much GDNF in the caudate nucleus, a brain region in which dopamine controls body movements. The calorie-restricted diet might also boost brain levels of another growth factor, brain-derived neurotrophic factor (BDNF). These results reinforce previous findings showing that exercise, which reduces damage to dopamine neurons in a rat model of Parkinson's, also boosts levels of GDNF and BDNF.

The findings with monkeys suggest that it may be possible to prevent Parkinson's disease in humans through diet, the researchers conclude. "However, the impact of calorie restriction and other dietary manipulations on the course of Parkinson's disease in patients who are already symptomatic remains to be determined."



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