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They collaborate. They share their toys. They're creative. They're psyched. The Center's 38 scientists from labs across this country and Europe are handpicked for their expertise in specific aspects of the search for the cure. Some also specialize in the new field of neuro-repair. Here we highlight a year of advances. PATHOLOGY 2007
When Astrocytes Go Wrong Wim Robberecht has found that a flaw in a body system for fine-tuning the nervous system likely accounts for a good bit of motor neuron destruction in one type of inherited ALS. His team has shown that the astrocytes that surround motor neurons in SOD1 animal models of the disease fail to signal motor neurons to protect themselves against deadly overstimulation—a common ALS event. In healthy animals, astrocytes somehow prod the motor neurons to add a protective subunit to receptors in their membranes. That added bit shields the neurons from a flood of calcium ions that ends in their overworking and death. The find suggests a therapy. Putting healthy astrocytes around motor neurons may reduce their vulnerability, says Robberecht. "That's easier than replacing motor neurons."
A Molecular Eraser Scientists note the frequent appearance of clumps or aggregates of "half-baked" SOD1 protein in cells in people and animal models of ALS. Any number of downhill events can result when aggregates appear. Val Culotta, using yeast cells, has shown that these immature forms of SOD1 are most prone to clump. And this year, her work suggests a way to fix mistakes in SOD1 maturation. She's discovered, in cell cultures, that the enzyme glutaredoxin not only increases the amount of "healthy" SOD1; it also decreases the undesirable clumping. Dangerous Uncoupling? The molecule semaphorin 3A (sema3A), rare in adult nervous systems, figures into their repair by halting overgrowth of injured nerve fibers. But Joost Verhaagen suggests that process may also occur in ALS as part of an unhappy molecular cascade that uncouples nerve cells from target muscles and hastens their death.
A clue came from the fact that in ALS, certain types of muscle fibers, called type IIb, are the first to be lost. And, in ALS mouse models, but not healthy mice, not only is sema3A plentiful at the neuromuscular junctions where nerves and type IIb muscle fibers meet, but receptors for the molecule are in good supply on motor neuron membranes. This, he believes, makes them fragile. It's the first suggestion how a difference between muscle fibers could be tied to ALS. Eye on the Other Half New grantee Jeffrey Macklis investigates the biology of the upper motor neuron "half" of ALS, a topic that's received little attention in the scientific community. By showing how stem cells morph into upper motor neurons, for example, his efforts could advance work to replace diseased neurons and enhance natural regrowth or, possibly, prevent neuron death. It could also help identify disease genes that target those neurons. THERAPEUTICS 2007
Ailing Astrocytes Jeffrey Johnson reports that it's possible to rev up a natural nerve-protective pathway, called Nrf2-ARE, in mouse models of ALS. Johnson focuses on the behavior of astrocytes—cells neighboring motor neurons—because they may be that path's major base of operations in normal tissues. "Sick" astrocytes from ALS models, however, apparently don't assist nerve cells. But turning up the protective path repairs astrocytes, for a complete reversal in tested cell cultures. "We're really excited about the possibility of saving motor neurons, first in mouse models," says Johnson. More Astroglia: Therapy Astroglia, cells that interact with motor neurons in the spinal cord, are a major focus in studies to find how ALS works, as well as how it can be slowed significantly or even repaired. The cells, which in many ways nurture motor neurons, lose that ability and become highly abnormal well before symptoms of any type of ALS appear. Reasoning that adding healthy astrocytes to injured tissues might be beneficial, Nicholas Maragakis and Mahendra Rao have used their expertise in growing immature and mature astroglia from their stem cell precursors. This year, they've shown that cells injected into spinal cords of animal models not only survive and have a right relationship with motor neurons, but they significantly increase the animals' survival. Vaccine Update
Last year, Jean-Pierre Julien discovered that in people with one form of the familial sort of ALS and in the animal models it's helped create, warped SOD1 protein is ushered out of cells. And just having an odd protein in an unusual place is enough to prompt an immune attack that kills motor neurons in lab cultures. That fact led Julien to the thought of trying to immunize against the protein. This year, he successfully carried out that process in mouse models: Various types of vaccines delayed disease onset and extended their lifespan. ANIMAL MODELS 2007 Transport Gone Awry Recent studies fuel the idea that flaws in the flow of nutrients and other matter throughout neurons—axonal transport, it's called—may underlie all motor neuron disease. Last year, Philip Wong and Fiona Laird, on Wong's team, developed a mouse model of transport gone awry, using a mutant gene for the protein dynactin, a protein cog in the system. In both symptoms and pathology, the animals uncannily mimic ALS. This year, Mohamed Farah joined the team in clarifying mouse model pathology on all levels. Most interesting: They suggest a huge disposal problem at work—that warped axon transport can disrupt the way cells normally clear "spent" organelles. No Junction Function
In the hunt for the earliest ALS event in the body—something that could shed light on the disease's trigger— research has turned to the zone between motor neurons and the muscles they target: the neuromuscular junction. It's a place that's impaired in ALS, but is it the disease's primary target? Studying the nature and timing of events there, of course, is impossible in patients, so Weichun Lin developed a new mouse model of ALS based on altering a natural complex of proteins so it disrupts the neuromuscular junction. His VAMP-synaptobrevin2 mice also have adult-onset motor neuron loss and paralysis, as in ALS, that follows the early damage. |
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