An experiment involving the eyes of flies offers a promising example of how research on model organisms may lead to new types of treatment for human diseases—even for such seemingly hopeless ones as Alzheimer and others that result from damaged or dying brain cells.

Flies were chosen for this experiment because, as Nancy Bonini, HHMI investigator at the University of Pennsylvania explains, "late-onset, progressive diseases such as Alzheimer or Parkinson can take months or years to develop in mouse models, but in flies they take only 10 days."

Bonini focused on a group of inherited brain diseases that are caused by a peculiarly large number of repeats of the DNA triplet CAG, which codes for the amino acid glutamine. These diseases include Huntington, which killed the folksinger Woody Guthrie; spinocerebellar ataxia type 3 (SCA3, also known as Machado-Joseph disease); and at least six other ailments that typically begin in adulthood. In each case, people whose gene has fewer than 35 CAG repeats stay healthy, while those whose gene typically contains more than 40 repeats become ill. Apparently the proteins that result from this excess of glutamine cannot fold into their proper shapes. As a result, they become toxic to neurons and slowly kill them off.

The experiment showed how such proteins can be helped to recover their normal shapes. Bonini and her colleagues at the University of Pennsylvania and the University of Iowa knew that a special class of proteins, called chaperones, has the job of guiding other proteins toward their proper structure. Would an extra supply of these chaperones prod the proteins into line sufficiently to prevent them from becoming toxic to neurons?

To find out, the researchers first made transgenic flies that contained the human SCA3 gene—and the flies' retinas rapidly degenerated. Next they made flies with both the SCA3 gene and a gene for a human chaperone protein, HSP70. This led to a dramatic rescue: The chaperone suppressed the disease and the eye looked normal again (see photo below, right).

"Many different human neurodegenerative diseases appear due to toxic protein structure," Bonini says, "so these findings may apply to a large number of disorders."

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A normal Drosophila eye with regular structure and full pigment. The cells in each of the eye's 800 identical units are arranged in a precise pattern.

Many of this transgenic fly's retinal neurons are sick and its retina has degenerated because of toxic proteins made by an inserted human SCA3 gene.

After treatment—an extra supply of chaperone proteins—the fly's eye appears normal externally and its internal structure is largely restored.

Photos: John M. Warrick, H.Y. Edwin Chan, Gladys L. Gray-Board, Yaohui Chai, Henry L. Paulson, and Nancy M. Bonini, Nature Genetics, vol. 23, p. 426, fig. 2, December 1999, ©1999 Nature America Inc.

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