MONDAY, Jan. 29, 2007 (HealthDay News) -- Tiny worms are revealing important clues to ataxia, a rare, debilitating neurodegenerative disorder that may have affected President Abraham Lincoln.
A new study suggests that the defective gene behind spinocerebellar ataxia type 5 (SCA5) causes nerve cells to snap under the strain of everyday movement and eventually die.
Last year, researchers at the University of Minnesota used DNA from Lincoln's descendants to pinpoint a defect in a particular gene as the cause of SCA5. Nearly one-third of the 299 descendants studied already showed symptoms of the illness.
The very rare disease, which has no cure, typically begins later in life and causes a gradual loss of coordination over time that leaves many patients wheelchair-bound.
Eyewitness accounts noted the older Lincoln's "shambling, loose, irregular, almost unsteady gait," typical of early stage SCA5. While there is no conclusive proof that the 16th president suffered from the illness, Lincoln's grandmother or grandfather did carry the defective gene, experts say, giving him a 25 percent chance of being affected.
Now, a team of researchers at the University of Utah says its study using the Caenorhabditis elegans worm -- a common animal model for research -- points to a novel mechanism driving SCA5.
According to the study, the implicated gene mutation may cause axons -- the long, skinny arms that extend out from nerve cells -- to become much less flexible and then break as an organism moves about.
"The structure of the neurons is normal during development and at birth, but it progressively deteriorates over time. And, when we looked closely at this, we found that it is deteriorating because the axons break," said senior researcher Michael Bastiani, professor of biology at the University of Utah's Brain Institute in Salt Lake City.
His team published its findings in the Jan. 29 issue of the Journal of Cell Biology.
This slow but steady breakage and re-breakage of axons eventually causes nerve cells to lose their ability to regenerate, Bastiani said. This could explain why the loss of coordination and gradual disability seen in SCA5 doesn't really begin to appear until late childhood or even much later in adulthood, he added.
The finding could have broader implications, as well. "The main excitement for me is that it points to a completely novel mechanism for neurodegeneration," Bastiani said. Axonal breakage could play a role in a variety of other neurodegenerative disorders, he theorized, although much more research is needed to prove that. "It's something that we really need to pay attention to," he said.
Certainly, this theory has competition when it comes to explaining SCA5. In fact, the University of Minnesota team that discovered the mutant gene responsible for the disease has its own, very different hypothesis.
Reporting last year in Nature Genetics, researchers at the university's Institute of Human Genetics pinpointed the cause of human SCA5 as a defect in a gene responsible for the production of an important cellular protein called beta-spectrin.
Laura Ranum, a professor of genetics, cell biology and development, led the study. According to Ranum, the mutated gene triggers a toxic build-up of glutamate inside nerve cells that eventually kills them.
But Bastiani's group now offers a different theory.
In the new study, he and co-researchers Erik Jorgensen and Marc Hammarlund focused on C. elegans, a one-millimeter-long worm that is a favorite of research biologists because it has genetic similarities to humans.
The Utah group designed a mutant form of C. elegans that was unable to produce beta-spectrin. Beta-spectrin plays a key role in helping various proteins "find their place" within nerve cells, Bastiani explained.
His team noticed no changes in the development of the worm's nervous system, "but as the animals age, there is this progressive deterioration," Bastiani said. "They become more and more uncoordinated, and finally they die."
Closer investigation suggested that the long, skinny axons that branch away from the worm's neurons were unable to take the strain of normal muscular movement and broke. These broken cells then tried to regenerate, "but every time they regenerated, they made more and more errors and, eventually, they were not able to grow back at all," Bastiani said.
"The clincher," he said, came when the researchers induced paralysis in the mutant worms. "In those cases, the axons no longer broke, and the nervous system looked almost normal. That was the test that it was the stress of muscular contraction that was really the cause of the breakage."
The Utah researchers' theory, while compelling, does have its flaws when it comes to explaining human SCA5, Ranum said.
"C. elegans is a wonderful tool for research," she said, "but the human situation is a bit more complicated. There are four beta-spectrin genes in humans, and there's only one in the C. elegans worm that they are studying."
Ranum also pointed out that the model used by the Utah group triggered a loss of the beta-spectrin protein, but in humans, "our protein is not missing." Instead, in human cases of SCA5, the protein is there but in a mutated form.
Still, Ranum said these and other findings are definitely worth pursuing. "What we need to do next is to develop other [animal] model systems" for SCA5 that are a bit closer to humans, such as the mouse, she said.
Unfortunately, effective treatment still remains a long way off. "The answer is still, 'No, there is not a cure,' " Ranum said.
But research continues, bolstered in part by SCA5's illustrious link to the White House. "I think that the connection to President Lincoln might increase the attention that studies are given," she said.
More information
Find out more about SCA5 and other ataxias at the National Ataxia Foundation.
