Scientists Find New Causes For Neurodegeneration - By U-M Scientists

A small region of a mutant mouse brain magnified 1000X. In the normal tissue the cells are tightly packed with no gaps, but in the mutant there are large holes due to loss of neurons from absence of the molecule PI(3,5)P2 from suppression of the Vac14 gene. (Credit: Image courtesy of University of Michigan)

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Diseases that cause neurons to break-down, such as Alzheimer's, Multiple Sclerosis and Creutzfeldt-Jakob disease (Mad Cow Disease), continue to be elusive to scientists and resistant to treatments.

A new finding from University of Michigan researchers demonstrates an unpredicted link between a virtually unknown signaling molecule and neuron health.

In a study in PNAS, graduate student, Yanling Zhang, postdoctoral fellow Sergey Zolov and Life Sciences Institute professor Lois Weisman connect the loss of this molecule to massive neurodegeneration in the brain.

The molecule PI(3,5)P2 is a lipid found in all cells at very low levels. Lipids are a group of small organic compounds. While the best studied lipids are fats, waxes and oils, PI3,5P2 is a member of a unique class of lipids that signal the cell to perform special tasks.

Weisman said it was surprising to find that PI(3,5)P2 plays a key role in the survival of nervous system cells.

"In mice, lowered levels of PI(3,5)P2 leads to profound neurodegeneration," said Weisman. "It suggests that we have a good place to look to find treatments for neurodegenerative diseases such as Alzheimer's."

Weisman, who is also professor of Cell & Developmental Biology at the U-M Medical School and her colleagues, began from clues that were hidden in a conserved genetic pathway in yeast (a pathway that has remained the same in yeast, plants and humans over evolutionary time). Studies in yeast showed that the enzyme that manufactures the lipid is governed by the FIG4 and VAC14 genes, which exist in yeast, mice and humans.

Working with two independently derived mouse models, Weisman's team and collaborators including graduate student Clement Chow and Professor Miriam Meisler of the Department of Human Genetics at the U-M Medical School, reached the same conclusions in a pair of important papers for neuroscience research.

Building on research from Meisler, a mouse geneticist, and Weisman, a yeast geneticist, the collaborators published a paper in Nature, July 5, 2007, showing that in mice, the FIG4 gene is required to maintain normal levels of the signaling lipid and to maintain a normal nervous system. Importantly, they found that human patients with a very minor defect in their FIG4 genes had serious neurological problems.

The signaling lipid PI(3,5)P2 (short for phosphatidylinositol 3,5-bisphosphate) is part of a communication cascade that senses changes outside the cell and promotes actions inside the cell to accommodate to the changes.

Weisman's team found that mice missing the VAC14 gene, which encodes a regulator of PI(3,5)P2 levels, suffer massive neurodegeneration that looks nearly identical to the neurodegeneration seen in the FIG4 mutant mice. In both cases the levels of PI(3,5)P2 are one half of the normal levels. The fact that both mice have half the normal levels of the lipid and also have the same neurodegenerative problems provides evidence that there is a direct link between the lipid and neuronal health.

The new findings indicate that when Vac14 is removed, the cell bodies of many of the neurons appear to be empty spaces and the brain takes on a spongiform appearance

Technorati : Neurodegeneration, U-M Scientists, brain scice

Space Station Has Power System Damage

This image provided by NASA television shows the hatch opened on the Quest airlock and astronaut Scott Parazynski waiting to exit on the second space walk of the mission early Sunday Oct. 28, 2007. (AP Photo/NASA

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Two spacewalking astronauts unhooked a 35,000-pound girder from the international space station Sunday, starting the delicate process of moving the giant solar power tower to another part of the orbiting outpost.

Spacewalkers Scott Parazynski and Daniel Tani started their 6 1/2-hour jaunt by disconnecting cables and unscrewing bolts that connected the girder to the space station's backbone.

Spacewalking astronauts found evidence of damage to a key part of the International Space Station's power system today.

It was the second of five scheduled spacewalks during the shuttle mission. More than six hours of outdoor activities were originally to be devoted to unbuckling an solar array atop the International Space Station so it could be moved to the side of the station, and also doing some work on the new "Harmony" module that astronauts had installed earlier in the week and first entered on Saturday.

Those tasks proceeded well, as has virtually everything else in this otherwise exceptionally smooth mission. But those successes could well be overshadowed by the discovery of iron shavings in one of the shuttle's enormous rotating joint assemblies.

The part, known as the Solar Array Rotating Joint, or SARJ, is 10 feet across and one sits toward each end of the station's long truss. The motorized joint allows solar panels to rotate and constantly face the sun during the sunny part of each orbit.

"It's quite clear," said Daniel Tani, one of the two spacewalkers, describing what he saw after removing a protective cover over a motor. "There's metal-to-metal scraping, or something, and it's widespread."

A sharp-eyed space station flight controller had recently noticed that the joint on the right side of the station was experiencing unusual vibrations as it rotated. Further examination revealed that the motor on that joint was using greater-than-expected amounts of current, which suggested that it was having to work harder than it should to turn the paddlewheel-like array. Mission managers added the inspection to the spacewalk schedule on Friday.

The shavings suggest that moving parts may be misaligned and grinding against each other, or perhaps that a piece of debris from the ground or from space may have gotten into the works. Mission managers had hoped the problem with the rotary joint would be easy to spot and easy to fix - something like a bolt out of place or an insulating blanket that was dragging and increasing friction, or even a leftover shop rag that was carried up to space and became lodged in the wrong place but could be removed. Before taking the cover off, Mr. Tani conducted a visual inspection of every bolt and blanket on the exterior of the device, which was made by Lockheed Martin at its Space Systems facility in Sunnyvale, and found no problems.

The problem could have ripple effects that go beyond this mission. If NASA wants a second look at the joint, a second spacewalk will have to be added to the schedule. With five spacewalks already on the shuttle mission's calendar, it would be difficult to squeeze in another. At the same time, the days between the end of this shuttle mission and the arrival of the next shuttle in December is packed with activities for the three-person space station crew, and so even a single additional spacewalk could mean delaying the December mission.

Kirk Shireman, the deputy space station program manager at the Johnson Space Center in Houston, noted said in a media briefing on Friday that there are backup motors and controllers for each rotary joint, and so the system might still be able to work after a switchover.

During the same briefing, Derek Hassman, the lead space station flight director, said that the troubled joint could be "parked" in a position that allows it to pick up a fair amount of sunlight throughout the orbit while NASA continues to investigate the problem. "As long as we can get it into an attitude that's reasonably good for power generation, combined with what the other SARJ can produce, we wouldn't have any significant power impacts that we couldn't deal with," he said.

Technorati : Space Station, nasa, news