Two genes that cause familial ALS shown to work together

September 1, 2011, Columbia University Medical Center

Although several genes have been linked to amyotrophic lateral sclerosis (ALS), it is still unknown how they cause this progressive neurodegenerative disease. In a new study, Columbia University Medical Center (CUMC) researchers have demonstrated that two ALS-associated genes work in tandem to support the long-term survival of motor neurons. The findings were published in the September 1 online edition of the Journal of Clinical Investigation.

"Any therapy based on this discovery is probably a long way off. Nonetheless, it's an important step toward piecing together the various factors that contribute to ALS," says lead author Brian McCabe, PhD, assistant professor of & cell biology in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain and a member of the Center for Motor Neuron Biology and Disease at Columbia University Medical Center (CUMC).

ALS, also known as "Lou Gehrig's disease," is a progressive disease that affects motor neurons — specialized nerve cells in the spinal cord and brainstem essential for controlling muscle strength and movement. ALS typically begins after age 50, eventually affecting one's ability to move, speak, and breathe. Some 30,000 Americans suffer from ALS at any given time. About 90 percent have a sporadic, or noninherited, form of the disease. The cause of sporadic ALS is unknown but likely involves a combination of genetic and environmental factors. The remaining 10 percent have a familial form of ALS, which is caused by an inherited genetic mutation. There is no cure for ALS. Symptoms are managed with medication, physical and speech therapy, assistive devices, and nutritional support. Many people with ALS die of respiratory complications within two to three years of diagnosis.

In the current experiment, the researchers examined the roles of two recently discovered ALS genes, FUS/TLS and TDP-43. Both genes are involved in the processing of messenger RNAs, which carry the genetic codes to make particular proteins. "The two genes make proteins with similar form and function, which suggested to us that they could work together, and that disruptions of either gene would affect neuronal survival," says Dr. McCabe. A competing view was that mutations to these genes cause abnormalities in their respective proteins that are toxic to independent of their normal functions.

To determine which model is correct, the researchers turned to the fruit fly (Drosophila melanogaster), which has genes similar to FUS/TLS and TDP-43 and reproduces quickly, making it a good model for genetic studies of ALS. For the study, Dr. McCabe's team created a line of flies with mutant FUS/TLS; flies with mutant TDP-43 had already been developed by an Italian research group.

In the first part of the study, the researchers found that flies with mutant FUS/TLS have decreased adulthood viability, diminished locomotor speed, and reduced longevity, compared with normal flies. The mutant flies were rescued (returned to normal) by inserting normal human FUS/TLS into their genome. The mutant flies were not rescued with ALS mutant human FUS/TLS. "This means that the gene works similarly in flies and in humans," says Dr. McCabe.

Flies with mutant TDP-43 showed similar deficits in survival, locomotion, and longevity. This line of flies was rescued with insertion of normal human TDP-43.

To determine whether the two genes interact, the team attempted to cross-rescue FUS/TLS or TDP-43 mutants by forcing overexpression of the other gene. Overexpression of FUS/TLS rescued flies with TDP-43 mutations, while overexpression of TDP-43 did not rescue flies with FUS/TLS mutations. "This finding demonstrates that FUS/TLS acts together with, and downstream of, TDP-43 in a common genetic pathway in neurons."

Whether these findings can be translated into therapy remains to be seen. "But one could imagine that if you could develop a drug or gene therapy that could make FUS/TLS more active, it might help in patients who have TDP-43 mutations," says Dr. McCabe.

"Our results show that these two genes work together in a familial ALS model," Dr. McCabe adds. "How ALS genes cause disease, and whether other genes work together, are big questions. The hope is that if we can eventually understand how all ALS interact, we can figure out how to intervene."

Dr. McCabe's paper is titled, "The ALS-associated proteins FUS and TDP-43 function together to affect Drosophila locomotion and life span." The paper's first authors are Ji-Wu Wang and Jonathan R. Brent at CUMC. Their coauthors include Andrew Tomlinson and Neil A. Shneider, also at CUMC.

Explore further: New discovery may block ALS disease process

Related Stories

New discovery may block ALS disease process

April 19, 2011
New Orleans, LA –In the first animal model of Amyotrophic Lateral Sclerosis (ALS), developed by Dr. Udai Pandey, Assistant Professor of Genetics at LSU Health Sciences Center New Orleans, Dr. Pandey's lab has found in ...

Studies of mutated protein in Lou Gehrig's disease reveal new paths for drug discovery

April 26, 2011
Several genes have been linked to ALS, with one of the most recent called FUS. Two new studies in PLoS Biology, one from the University of Pennsylvania School of Medicine, and the other from colleagues at Brandeis University, ...

Researchers make strides in understanding amyotrophic lateral sclerosis

April 26, 2011
Brandeis researchers have made a significant advance in the effort to understand amyotrophic lateral sclerosis (ALS) by successfully reversing the toxicity of the mutated protein in the familial type of the disease.

Recommended for you

Peers' genes may help friends stay in school, new study finds

January 18, 2018
While there's scientific evidence to suggest that your genes have something to do with how far you'll go in school, new research by a team from Stanford and elsewhere says the DNA of your classmates also plays a role.

A centuries-old math equation used to solve a modern-day genetics challenge

January 18, 2018
Researchers developed a new mathematical tool to validate and improve methods used by medical professionals to interpret results from clinical genetic tests. The work was published this month in Genetics in Medicine.

Can mice really mirror humans when it comes to cancer?

January 18, 2018
A new Michigan State University study is helping to answer a pressing question among scientists of just how close mice are to people when it comes to researching cancer.

Group recreates DNA of man who died in 1827 despite having no body to work with

January 16, 2018
An international team of researchers led by a group with deCODE Genetics, a biopharmaceutical company in Iceland, has partly recreated the DNA of a man who died in 1827, despite having no body to take tissue samples from. ...

Epigenetics study helps focus search for autism risk factors

January 16, 2018
Scientists have long tried to pin down the causes of autism spectrum disorder. Recent studies have expanded the search for genetic links from identifying genes toward epigenetics, the study of factors that control gene expression ...

The surprising role of gene architecture in cell fate decisions

January 16, 2018
Scientists read the code of life—the genome—as a sequence of letters, but now researchers have also started exploring its three-dimensional organisation. In a paper published in Nature Genetics, an interdisciplinary research ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.