BioWorld International Correspondent

LONDON - The discovery of new genetic mutations responsible for some cases of amyotrophic lateral sclerosis (ALS) will refocus research into the causes and treatment of the fatal neurodegenerative disease.

The study of a family with several members affected by ALS has allowed scientists to pinpoint mutations in a gene called TARDBP, which encodes a protein called TDP-43.

That study provided evidence to support the view that accumulation of TDP-43 in the motor neurons of people with ALS is a cause of the disease, and not just a by-product of dead or dying nerve cells.

Christopher Shaw, professor of neurology and neurogenetics at the Institute of Psychiatry, King's College London, told BioWorld International: "TDP-43 accumulates in the brains of 95 percent of people with ALS, but there has been a huge debate among researchers about whether this accumulation is toxic. Our finding of rare mutations in the gene encoding TDP-43 now places this protein back in the center stage as a potential cause of motor neurodegeneration."

The finding should assist those working to find new therapies for ALS, he predicted. "This discovery will give scientists around the world a new tool to explore the disease process in ALS, and hopefully this will accelerate drug discovery."

A report of the study appears online in the Feb. 28, 2008 edition of Sciencexpress, in a paper titled: "TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis."

Between one and three people in every 100,000 develop ALS, usually in their late 50s to early 60s. The first symptoms are muscle weakness, caused by the death of motor neurons. The disease is progressive and ultimately spreads throughout the body, including the respiratory muscles. There is no treatment, and people with ALS normally die within three years of the onset of symptoms.

About 5 percent to 10 percent of ALS cases are familial, but the rest are sporadic. Earlier studies have found that a mutation in the SOD1 gene is responsible for approximately 5 percent of all cases, but people with ALS due to the SOD1 mutation do not accumulate the TDP-43 protein in their motor neurons.

Shaw and his colleagues set out to investigate what role TDP-43 has in ALS. They first screened 154 unrelated people who had the familial form of ALS, looking for mutations in TARDBP, the gene that encodes TDP-43. People with a mutation in SOD1, and other known mutations associated with ALS, were excluded from the study.

They were in luck. One of their subjects had a missense mutation in TARDBP. Further investigations showed that this mutation was present in four members of the person's family who had ALS, and absent from nine unaffected family members.

Next, Shaw and his colleagues screened the whole genome of all members of the kindred, and were able to show that the only region that all affected members of the family shared was the region where TARDBP is located.

The researchers then looked for mutations in the TARDBP gene in large groups of people with ALS and even more controls. They identified a further two mutations in the affected group, bringing the number of mutations in TARDBP in 526 people with ALS to three, while the number of mutations in TARDBP in 1,262 healthy controls was zero.

They then carried out further experiments to investigate the effect of the mutant genes on cells in culture. Abnormal proteins derived from two of the mutant genes the researchers had identified were more likely to fragment in the cells than the normal wild-type protein.

Finally, they delivered the mutated genes to nerve cells in a chick embryo model of spinal cord development. "We saw the spinal cord degenerate quite dramatically with the mutant proteins but not with the wild type, so the mutant protein was toxic to these developing nerve cells," Shaw said.

The results suggested, he added, that the accumulation of TDP-43 may well be pathogenic. "This discovery gives us a biological tool we can use to investigate the mechanism of pathogenesis," Shaw said. "We will now put these human mutant genes into flies, fish and mice, and try to model the disease. Our aim is to develop a model - either cellular or animal - that will allow scientists to screen compounds for potential therapeutic action."