IMAGE: Pamela Maher is a researcher at the Salk Institute for Biological Studies.
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In earlier studies, Pamela Maher, Ph.D., a senior staff scientist in the Salk Cellular Neurobiology Laboratory, had found that fisetin exerted its neuroprotective and memory-enhancing effects through the activation of the Ras/ERK signaling pathway.
"Because Ras/ERK is known to be less active in HD, we thought fisetin might prove useful in the condition," Maher
team began their study by looking at a nerve cell line that could be made to express a mutant form of the huntingtin protein.
Without treatment, about 50 percent of these cells will die within a few days.
Adding fisetin, however, prevented cell death and appeared to achieve it by activating the Ras-ERK cascade.
The researchers then turned their attention to Drosophila.
In collaboration with J. Lawrence Marsh, Ph.D., a professor of developmental and cell biology at the University of California, Irvine
tested fisetin in fruit flies overexpressing mutant huntingtin in neurons in the brain.
The affected flies don't live as long as normal flies and also have defective eye development.
When they were fed fisetin, however, the HD flies maintained their life span and had fewer eye defects.
team tested fisetin's effects in a mouse model of HD.
HD mice develop motor defects early on and have much shorter life spans than normal control animals.
team fed them fisetin, the onset of the motor defects was delayed, and their life span was extended by about 30 percent.
"Cells are damaged and dying before there are overt symptoms," Maher
"If patients know they have the mutation, then they could potentially start treatment before they start showing symptoms, which might be more effective than waiting for the symptoms to appear, as many do now."
Maher's lab has developed a variety of fisetin derivatives that are more potent in cell-based assays than the fisetin used in the study, and she
plans further tests to see which combination is most effective in HD and other neurodegenerative disorders.
In the meantime, does she
recommend eating a lot of strawberries to gain fisetin's benefits?
"It probably couldn't hurt," she
In addition to Maher and Marsh, Richard Dargusch of the Salk Institute and Laszlo Bodai, Paul Gerard and Judy Purcell of the University of California, Irvine, contributed to the study.