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Posted on Wed, Jun. 13, 2007
Trash haulers for the sick brain
By Tom Avril
INQUIRER STAFF WRITER

University of Oklahoma
Plaques eventually kill brain cells, leading to the progressive loss of memory and brain function that debilitates and kills Alzheimer's patients.
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Fruit flies with neurodegenerative disease
Diseases that ravage the nervous system - Alzheimer's, Huntington's, Lou Gehrig's and so on - are marked by a toxic buildup of faulty proteins, overwhelming our cells' natural ability to take out the trash.
Today, University of Pennsylvania researchers said they had made headway with what might seem like an obvious idea: sending more cellular trash trucks to the rescue.

Through sophisticated genetic manipulation, the scientists got this trick to work for five such diseases in fruit flies, and have begun experimenting on mice. The results are reported in tomorrow's issue of the British journal Nature.

Medical research is littered with examples of potential treatment pathways that looked promising in lab animals but hit a dead end when tried in more complex human patients. Yet the new approach takes advantage of cellular machinery that is already known to exist in people, offering hope that these killer diseases might someday be attacked with a universal weapon.

At the very least, the paper's authors are helping to solve a longstanding mystery about the workings of the cell.

The machinery they exploited is called autophagy, from Greek roots that mean "self-eating." It is a process in which the cell forms bubble-like vacuoles around some of its worn-out parts. The bubbles then fuse with a cellular apparatus called the lysosome, which chops up the trash and spits it out for recycling.

Scientists have known about these vacuoles since at least the 1950s, when they were found in mice kidneys. But the process remains poorly understood. Until recently, it had received so little study that there's still no consensus on how to pronounce it.

The new paper's senior author, Penn neurogeneticist J. Paul Taylor, favors "AUTO-fay-gee." Some scientists say "aw-TOFF-uh-gee."

However you say it, the word is now the title of a new academic journal, founded in 2005 in response to a flurry of research. The discovery that autophagy might be harnessed to fight brain diseases, for example, has emerged only in the past few years, said journal editor Daniel J. Klionsky, a University of Michigan life sciences professor.

"The results are just so tantalizing," Klionsky said of ongoing research by Taylor's lab and others. "We have to continue working in this area."

In tomorrow's Nature paper, the Penn team said it had used autophagy to "rescue" fruit flies after engineering them to develop versions of these human neurodegenerative diseases.

One is a rare ailment called Kennedy's disease, which attacks neuron cells and causes muscle deterioration. Like humans with the disease, the mutant insects had difficulty getting around, said Udai Bhan Pandey, Taylor's post-doctoral fellow and the paper's lead author. The impaired behavior is evident in a lab video of flies trying to climb up a wall.

Using a subtle genetic trick, Pandey also created flies that expressed the disease only in their eyes. That way, he could tell at a glance whether they were healthy or not.

After months of carefully breeding engineered flies, the scientists identified a key gene that seems to communicate between the cell's two systems of trash disposal: autophagy and another called the proteasome.

The proteasome - a cylindrical trash compactor in the cell - is unable to digest large clumps of "misfolded" and worn-out proteins that are common in neurodegenerative disease. So the scientists boosted levels of autophagy instead, adding extra copies of the key gene to compensate.

This strategy worked in flies with the mutation for Kennedy's, Alzheimer's and three other diseases, Taylor said. It also worked for several more disorders when they applied it to individual cells in a lab dish.

"We can just shovel just about anything over to the autophagy," said Taylor, who collaborated with scientists at Duke, Stanford, the University of Maryland, the National Institutes of Health, and Novartis Institutes for Biomedical Research.



Contact staff writer Tom Avril at 215-854-2430 or tavril@phillynews.com