December 2001

From University of Pennsylvania

Penn team finds 'molecular chaperones' can halt progress of Parkinson's disease in fruit flies and possibly humans

PHILADELPHIA Ė Using fruit fly models of Parkinsonís disease, researchers at the University of Pennsylvania have found that a class of proteins known as "molecular chaperones" can block the progression of neurodegenerative disease in Drosophila melanogaster. In addition, the group has found evidence that similar pathways may operate in Parkinsonís disease and possibly other neurodegenerative disorders in humans.

The findings will be published in the journal Science, as part of its Science Express web site, on Dec. 20. They suggest that activation of molecular chaperones may be an effective approach in the treatment of several human neurodegenerative diseases, senior author Nancy M. Bonini said.

"Our work indicates that up-regulation of a molecular chaperone called Hsp70 can prevent neuronal decay in a fruit fly model of Parkinsonís disease," said Bonini, Penn professor of biology and investigator with the Howard Hughes Medical Institute. "Weíve also found some of the same molecular chaperone pathology in tissue taken from people with Parkinsonís disease, suggesting that these molecules may play the same role in humans as in flies."

Bonini and colleagues in Pennís School of Medicine also found molecular chaperones in tissue from people afflicted with other neurodegenerative diseases associated with similar protein pathology, including a variant of Alzheimerís disease.

"These data suggest that altered chaperone activity may be involved in the progression of Parkinsonís disease, and that chaperones such as Hsp70 may be a critical part of the neuronal arsenal that fights neurodegenerative disease," said Pavan K. Auluck, a Penn M.D./Ph.D. student who is lead author on the Science paper.

Parkinsonís disease is the second most common human neurodegenerative disorder, characterized by tremors, postural rigidity and progressive deterioration of dopaminergic neurons in specific areas of the brain. Despite the evolutionary gulf separating humans and fruit flies, neurotoxicity unfolds in a similar manner in both species. Like humans, Drosophila melanogaster experiences neuronal loss upon expression of alpha-synuclein, a protein implicated in the onset of Parkinsonís disease in both species.

"We observed that flies expressing alpha-synuclein had lost about half their dopaminergic neurons in specific brain areas by 20 days of age," Bonini said. "But when alpha-synuclein and Hsp70 were expressed simultaneously, these aged fruit flies exhibited normal numbers of these neurons. In fact, in the presence of Hsp70, the same number of neurons were present at 20 days of age as in flies just one day old."

In another group of flies, the Penn team suppressed the activity of a Drosophila protein analogous to Hsp70, known as Hsc4, and found that these flies showed enhanced sensitivity to alpha-synuclein, with marked neural degeneration at just one day of age. Both Hsp70 and Hsc4 are thought to function by untangling misfolded proteins, mitigating the harmful effects of inappropriately configured proteins.

"These studies emphasize the sensitivity of dopaminergic neurons to chaperone levels and suggest that endogenous chaperones may normally protect against alpha-synuclein toxicity by delaying the onset of degeneration," Auluck, Bonini and their colleagues write in Science.

The Penn researchers studied neural decay among flies expressing alpha-synuclein by tagging and counting numbers of dopaminergic neurons, the same type of neurons that degenerate in Parkinsonís disease in humans.

Auluck and Bonini were joined on the Science paper by H.Y. Edwin Chan, a postdoctoral researcher in the Bonini lab, and John Q. Trojanowski and Virginia M.-Y. Lee, both professors of pathology and laboratory medicine in Pennís School of Medicine and co-directors of Pennís Center for Neurodegenerative Disease Research. The work was funded by grants from the David and Lucile Packard Foundation, the National Institute on Aging, the National Institutes of Health and the Alzheimerís Association.












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