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April 6, 2007
Model of Accelerated Familial ALS Sheds Light on Disease Process
The devastated offspring from a mating of two types of laboratory mice—one of them a classic model of ALS, or Lou Gehrig’s disease—should pull scientists’ attention more strongly to the mitochondria, cell structures recently suspected as major players in the death of nerve cells in that illness.
The animals’ rapid decline—they unexpectedly succumbed almost six times faster than the usual ALS mouse model—suggests their potential to reveal flaws within mitochondria that can carry out ALS’s downhill course.
While what happens to patients with ALS is well described, the cause of the disease is not. That’s certainly true for its most common, or sporadic, form. One type of the rarer familial ALS, however—a type that affects about 20 percent of patients with the disease in their families—has somewhat clearer beginnings. There, the source of disease is a mutation in the gene for the common cell protein superoxide dismutase, or SOD1. But exactly how abnormal SOD1 leads to illness remains mysterious. And resolving that mystery, scientists say, would illuminate all forms of the disease.
In a study underwritten by the Packard Center for ALS Research, a team that includes neuroscientist Jeffrey Elliott at the University of Texas Southwestern Medical Center in Dallas and Packard neuroscientist Giovanni Manfredi at Cornell University, found increased amounts of mutant SOD1 within mitochondria, the cell’s chief energy supplier. Further, they found the higher amounts tied to mitochondrial destruction. And when mitochondria deteriorate, Manfredi and others showed earlier—and this study confirm—the animals undergo an ALS-identical decline.
A description of the work appears in this month’s Proceedings of the National Academy of Sciences.
“These unexpected findings strongly suggest that an early, very toxic event involves mitochondria in the familial form of ALS,” says Packard Director Jeff Rothstein. “This new observation helps explain the results of prior studies with diverse protective drugs—such as antioxidants, anti-glutamate agents, and anti-cell death cascade agents—since they all have a common element in improving the workings of mitochondria.”
This latest research stemmed, basically, from a curiosity to see what would result if ALS model mice—those carrying human genes for mutant SOD1—received an extra supply of a natural molecule that typically “adjusts” normal SOD1 from an immature to a mature form. Elliott induced overexpression of the natural CCS molecule in the model mice by breeding mice engineered to carry human CCS genes with the ALS model mice.
While model ALS mice typically develop symptoms at 180 days and succumb around 240 days, the dual-gene offspring mice sickened by day 11. Most survived barely a month. Microscope studies showed rampant irregularities, specifically in the mitochondria. “It’s hard to find a normal one in these mice,” says Elliott. Further study showed that typical chemical pathways in mitochondria—those for the cell respiration that produces energy—were also abnormal.
Most interesting, the scientists agree, was the fact that mutant SOD1 inside mitochondria was significantly higher in the dual gene mice than in normal mice and also higher than in ALS model mice without CCS. “So CCS is clearly doing something with abnormal SOD1,” says Manfredi, “but we don’t know what.”
Because the results are so drastic, adds Elliott, “we think we can use this as a tool to find out how mutant SOD1 goes on to change the way mitochondria function.” This sort of forcing the hand of disease, he says, may highlight pathway abnormalities that would otherwise be difficult to see.”
Support for the work came from the Packard Center for ALS Research at Johns Hopkins, the NIH, the Horace C. Cabe Foundation and other private sources.
Marjatta Son, Krishna Puttaparthi, Hibiki Kawamata, Bhagya Rajendran and Philip Boyer were part of the research team.
>>more Recent News
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for ALS Research: |
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| 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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