Scientists at Washington University School of Medicine in St. Louis have linked a mutation in a gene known as TDP-43 to an inherited form of amyotrophic lateral sclerosis (ALS), the neurodegenerative condition often called Lou Gehrig's disease.
Researchers found the connection intriguing because studies by other groups have revealed abnormalities in the TDP-43 protein in both sporadic and inherited ALS, as well as in several other neurodegenerative disorders.
"The potential link to sporadic ALS is particularly interesting. If we can confirm TDP-43's association with inherited ALS, mutating this gene may give us a way to model sporadic ALS in laboratory animals for the first time," says senior author Nigel Cairns, Ph.D., research associate professor of neurology and pathology and immunology. "That could give us a potent tool for better understanding ALS and developing new treatments."
The study appears February 20 in Annals of Neurology. It was conducted at the Hope Center for Neurological Disorders, a partnership between the University and Hope Happens, a St. Louis-based non-profit organization dedicated to raising funds for neurological research.
Approximately 30,000 U.S. citizens have ALS, a condition that kills motor neurons, the nerve cells that control muscles. This causes gradually increasing paralysis and typically leads to death over a course of several years. Approximately five to 10 percent of all ALS cases are inherited; the rest are sporadic.
Hope Happens was founded by Christopher Hobler, a St. Louisan who developed ALS and died from the disorder in 2005. Hobler's grandfather and cousin had previously died from the disorder, and Hobler and his family founded Hope Happens to promote awareness of ALS and other neurodegenerative conditions and to raise money for research to develop new treatments and cures.
In 1993, scientists linked an inherited form of ALS to mutations in the gene for a protein called superoxide dismutase-1 (SOD1). Since then, many had thought altering the SOD1 gene's function was the most promising way to model and understand sporadic ALS.
"That has all been turned upside down in the last two years, though," says Cairns. "In that time, abnormal TDP-43 deposits have been identified in sporadic ALS cases and in some inherited forms of ALS that don't involve a SOD1 mutation."
TDP-43 is an influential regulator of messenger RNA splicing, the process that edits protein-building instructions from DNA to allow the proteins to be built properly. TDP-43 abnormalities in ALS patients have included altered folding and a chemical change known as phosphorylation, both of which can radically alter the protein's function.