School of Medicine scientists 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,” said senior author Nigel Cairns, Ph.D., research associate professor of neurology and of pathology and immunology. “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. That could give us a potent tool for better understanding ALS and developing new treatments.”
The study appeared Feb. 20 in Annals of Neurology. It was conducted at the Hope Center for Neurological Disorders, a partnership between the University and Hope Happens, a local nonprofit organization that raises funds for neurological research.
About 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. About five percent 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 also died from the disorder. 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 thought altering the SOD1 gene’s function was the most promising way to model and understand sporadic ALS.
But that has changed in the past two years, Cairns said.
“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,” he said.
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.
As a result, several research groups have been looking for a case where a mutation in the TDP-43 gene was linked to inherited disease. This study is the first to tentatively establish such a link. Michael Gitcho, Ph.D., a postdoctoral research associate in Cairns’ lab, and colleagues found that every member of a family affected by an inherited form of ALS had a particular mutation in TDP-43. They looked at 1,505 people unrelated to the family and unaffected by ALS. This second search found no examples of the same mutation.
Because the family they studied is small, scientists need further evidence to confirm that the mutation is causing ALS. Researchers are working to introduce the mutated human TDP-43 gene they identified in the family into a mouse model.
What they learn may also shed light on other neurodegenerative disorders. Co-author Alison M. Goate, D. Phil., the Samuel and Mae S. Ludwig Professor of Genetics in Psychiatry, said abnormal TDP-43 has been found in patients with frontotemporal dementia, the second most common cause of early onset dementia after Alzheimer’s disease.