Researchers at Washington University School of Medicine in St. Louis have found that a gene linked to inherited amyotrophic lateral sclerosis (ALS) or Lou Gehrig's disease, may also play a role in dementia.
The gene in question has been identified as TDP-43.
The study is led by Nigel Cairns, Ph.D., research associate professor of neurology and pathology and immunology.
"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. That could give us a potent tool for better understanding ALS and developing new treatments," said Cairns.
ALS is a condition that kills motor neurons, the nerve cells that control muscles. This leads to gradually increasing paralysis and causes death over a course of several years. Almost 5 to 10 pct of all ALS cases are inherited and the rest are sporadic.
Researchers linked an inherited form of ALS to mutations in the gene for a protein called superoxide dismutase-1 (SOD1) in 1993. After that, many 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. 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," said Cairns.
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 include altered folding and a chemical change known as phosphorylation, both of which can drastically alter the protein's function. Thus, many researchers have been looking for a case where a mutation in the TDP-43 gene was linked to inherited disease.
The current study is the first to tentatively establish such a link. The researchers found that every member of a family affected by an inherited form of ALS had a particular mutation in TDP-43.
Later, they examined 1,505 people not related to the family and unaffected by ALS. No examples of the same mutation were found in this second search.
Scientists need further evidence to confirm that the mutation is causing ALS, as the family they studied is small. Work is going on to introduce the mutated human TDP-43 gene they identified in the family into a transgenic mouse model and the researchers are hoping that the mouse will generate a model for ALS-like pathology.
If the link gets affirmed, the researchers will start to trace the effects of the mutation on genes whose splicing is regulated by TDP-43, working to identify key links in the chain reaction that leads to motor neuron death. These links may become new targets for pharmaceutical treatments.
This may further explain other neurodegenerative disorders. According to the researchers, abnormal TDP-43 has been found in patients with frontotemporal dementia, the second most common cause of early-onset dementia after Alzheimer's disease.
"As our understanding of these diseases progresses, we're starting to see common elements. This protein may allow us to link together a number of important disease entities and pinpoint new targets for therapeutic intervention," said Alison M. Goate, one of the authors of the study.
The study appears in the recent issue of Annals of Neurology.