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May 3, 2007
Self-Attack? Self-Repair? The First Real Look at Gene Activity in ALS Models Sparks Thirst for Answers
The number one question in ALS research today is still: What triggers the destruction of motor neurons?
In an unusual approach to the answer — one that records what genes are expressed in the disease, when they’re expressed, and how intensely — Packard scientist Don Cleveland found some of the results satisfying: they intuitively made sense. Other finds were so surprising that they could push therapy studies in a new direction.
To have motor neurons turn on genes for central nervous system repair, for example, seems reasonable in an ongoing neurodegenerative disease. And it was more interesting than surprising, Cleveland says, to see an upturn in genes with a possible tie to excitotoxicity, the harmful overstimulation of motor nerves that likely occurs in ALS.
But other gene changes, Cleveland says, were “quite unexpected.” Activating those that tell motor neurons to take on characteristics of damaged or foreign bodies — to “squeal” on themselves, in effect, so the immune system can attack them — “is probably not healthy behavior,” he explains. “They’re in danger, then, of speeding up their own degeneration.”
This latter find, he says, is sure to spark more research focused on the interactions between motor neurons and microglia, the central nervous system’s resident immune cells.
In the study described this month in the journal, Proceedings of the National Academy of Sciences, Cleveland’s team including Christian Lobsiger and Severine Boilee, all of the University of California at San Diego, “profiled” some 30,000 genes from motor neurons in spinal cords of embryonic mice with an inheritable form of ALS. They also profiled genes in adult ALS mice, teasing out motor neurons from their spinal cords to study at intervals before symptoms typically occur. Comparing pre-birth and later ages, they reasoned, might catch the earliest cell changes, ones more likely to act as triggers.
By analyzing the 21 genes that most commonly show different patterns of activation from healthy mice, Cleveland’s team saw that these changes, and whatever they cause, don’t appear in embryonic motor neurons. Instead, gene changes seem to come as the animals age, but well before symptoms appear.
Most interesting to the researchers, though, is the apparent early activity in genes that produce proteins for what’s called the complement pathway, usually a part of a molecular brigade the immune system maintains to tag foreign or injured cells for removal. The early-ness of the event, for one thing — well before the peak of the harmful nervous system inflammation traditional in ALS — makes the scientists suspect its importance. “It’s likely part of the disease’s early toxicity in motor neurons” says Cleveland.
And its location — turning on genes for complement proteins within motor neurons rather than immune cells — is highly unusual, Cleveland adds, though recently a stirred-up complement system has been discovered in Parkinson’s and Alzheimer’s diseases.
In the ALS mice, one complement gene in particular invites study. The C1q snip of protein that it produces happens to be a traditional signal flag for the complement system to begin clearing debris or injured cells. Could motor neurons, in ALS, abnormally give the signal for destruction? “It’s a tempting thought,” he says.
So, he says, is the idea of therapy that considers these cell changes. “If we can suppress motor neurons from expressing C1q,” says colleague Lobsiger, “or somehow protect the neuron from the resulting immune attack, this could offer an isolated ALS therapy or one we might use in combination with others directed at the immune system.”
>>more Recent News
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| Recent news from the Robert Packard Center
for ALS Research: |
| William H. Adams Foundation Pumps New Energy, Funds into Search for ALS Cure - May 6, 2008 |
| Tell-Tale Protein Clumping in ALS is Less Complex Than Expected - April 10, 2008 |
ALS Mouse Study Highlights Astrocytes' Strong Potential as Therapy Target - February 7, 2008 |
| Exciting New Human ALS Trial: Lithium and Riluzole - February 7, 2008 |
| ALS Treatment: A Matter of Cleaning House? - December 19, 2007 |
New Study Brings What Goes Wrong in Inherited ALS into Focus - September 18, 2007 |
| New ALS Protein Could Be a Keystone - August 9, 2007 |
| Muscles More Than Passive Victims in ALS, Study Suggests - June 29, 2007 |
| Saer and O’Neill Named Packard Center Board Co-Chairs - June 28, 2007 |
Self-Attack? Self-Repair? First Real Look at Gene Activity in ALS Models Sparks Thirst for Answers - May 3, 2007 |
| Model of Accelerated Familial ALS Sheds Light on Disease Process - April 6, 2007 |
| Early News From First Large Search for Sporadic ALS Genes - February 20, 2007 |
| Human Stem Cell Transplants Mature Into Neurons and Make Contacts in Rat Spinal Cord - February 14, 2007 |
First Vaccine for Familial ALS Shows Potential in Model Mice - January 29, 2007 |
| Our Five-Year Plan? Let Human Cells EXcellerate Therapy - January 18, 2007 |
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