Rare TDP-43 mutations expose potential therapeutic target, experts say
THURSDAY, Feb. 28 (HealthDay News) -- Researchers have implicated a new, yet rare, genetic mutation in the development of amyotrophic lateral sclerosis (ALS).
The finding not only exposes a potential therapeutic target for treating the fatal neurodegenerative disease, it also confirms that this particular mutation sets in motion the mechanism that causes many cases of ALS.
The results provide "a link between genetics and [the] pathology that proves that the pathology is important for the disease," said Virginia Lee, a professor of pathology and laboratory medicine at the University of Pennsylvania School of Medicine, in Philadelphia.
The results were published in the Feb. 28 online edition of Science.
ALS, also known as Lou Gehrig's disease, is an incurable motor neuron disorder that affects some 30,000 Americans, according to the ALS Association. From 5 percent to 10 percent of those cases are inherited; the remainder are sporadic. Several genes have been associated with the disease, most notably SOD1, which accounts for about 20 percent of familial cases and 3 percent of sporadic ones.
The gene in the present study, TARDBP, encodes TDP-43, a gene involved in, among other things, RNA processing. In 2006, Lee's group discovered that TDP-43 is a pivotal gene in both ALS and a cognitive disorder called frontotemporal lobar dementia (FTLD).
The question was, were these TDP-43 mutations involved in disease pathology or merely a byproduct of it?
"What we needed was a 'smoking gun,' " said Lee."Can we find mutations in TDP-43 in ALS patients?"
Dr. Christopher Shaw, a professor of neurology and neurogenetics at King's College London, led an international team of researchers to find out.
Shaw studied the TDP-43 gene in 154 families with familial ALS. They discovered one family with a mutation in the gene, which was present in all affected family members, and absent in unaffected ones. The mutation changes just a single amino acid in the protein sequence. The team also found similar TDP-43 mutations in two additional, sporadic cases.
But merely finding a mutant gene in affected individuals does not automatically mean it causes disease. What is needed is proof these mutations induce a neurological disease akin to ALS. To address that question, the team expressed both normal and mutant TDP-43 in chick embryos.
"Much to our surprise, in 49 of 49 embryos [expressing the mutant TDP-43], chick spinal cord cells died, while if we injected the [normal] gene, we saw no death at all," said Shaw. "That tells us this tiny change in the gene is harmful. This isn't just an innocent variation, there is something the variation is doing that is harmful to cells."
"I think it's a very, very exciting finding," Lee said, especially in light of the recent publication in the Annals of Neurology of another case of familial ALS with a mutation in TDP-43.
Dr. Catherine Lomen-Hoerth, director of the ALS Center at the University of California, San Francisco, said the findings could aid ALS research and drug development.
"For a long time, we've only had one good genetic mouse model for the disease," she said, referring to the SOD1-based model. "I think this discovery provides the possibility of making a mouse model that might be very helpful to help understand both ALS and FTLD."
The two diseases "may represent opposite ends of a spectrum of the same disease," Lee explained.
Most ALS cases (except those caused by SOD1 mutations) exhibit TDP-43 mutations, Shaw said. Yet mutations in the gene appear to be relatively rare, at least based on their prevalence in the current study. What these latest findings do is provide "the first concrete link" between TDP-43 and disease pathology.
The situation is analogous to Alzheimer's Disease, he said, which is associated with beta-amyloid protein accumulation. Though relatively few Alzheimer's cases are actually caused by mutations in the amyloid protein gene, their discovery underscored the protein's role in disease pathology.
"It gives us a biochemical tool to recapitulate the disease process in animals, to begin to develop treatments," Shaw said. "And so, it is a really crucial weapon against the disease."
For more on amyotrophic lateral sclerosis, visit the ALS Association.
SOURCES: Christopher Shaw, M.D., Ph.D., professor, neurology and neurogenetics, King's College London; Catherine Lomen-Hoerth, M.D., Ph.D., associate professor, neurology, and director, ALS Center, University of California, San Francisco; Virginia Lee, Ph.D., professor, pathology & laboratory medicine, University of Pennsylvania School of Medicine, Philadelphia; Feb. 28, 2008, Sciencexpress online
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