Scientists block toxic protein that plays key role in Lou Gehrig's disease

October 28, 2012

October 28, 2012— Scientists at the Gladstone Institutes and the Stanford University School of Medicine have discovered how modifying a gene halts the toxic buildup of a protein found in nerve cells. These findings point to a potential new tactic for treating a variety of neurodegenerative conditions, including amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease)—a fatal disease for which there is no cure.

The Gladstone and Stanford scientists began their experiments independently before realizing that combining their efforts could strengthen their results. Their discovery—which involved the work of both neuroscientists and geneticists—underscores the importance of collaborative and cross-disciplinary research when dealing with complex such as ALS.

ALS usually strikes between the ages of 40 and 75, ravaging the body's motor neurons— that control muscle movement. This causes muscle weakness, difficulty swallowing and breathing, paralysis and, ultimately, death—often just three to five years after diagnosis. At any given time, as many as 30,000 Americans are living with ALS—which afflicts physicist Stephen Hawking and which killed baseball legend Lou Gehrig.

In a paper published today online in , researchers in the laboratories of Stanford Associate Professor Aaron D. Gitler, PhD, and Gladstone Senior Investigators Robert V. Farese, Jr., MD and Steve Finkbeiner, MD, PhD, describe how shutting off a gene called Dbr1 in and in neurons obtained from rats can protect both cell types from the toxic effects of TDP-43—a protein that plays a key role in ALS.

"Mutations in the gene that produces TDP-43 can cause this protein to build up in cells," said Dr. Farese, who is also a professor at the University of California, San Francisco, with which Gladstone is affiliated. "Over time, TDP-43 accumulation inside can reach toxic levels and bind to RNAs—small bits of genetic material that act as an intermediary between genes and proteins. One theory is that this binding interferes with the RNAs' normal functions and impairs the overall health of cells. Eventually, the neurons degrade and die, contributing to the rapid progression of ALS symptoms."

It was already known that TDP-43 contributes to ALS. But disabling this protein directly is not an option, as TDP-43 is vital for cell survival. However, too much of it is toxic. So the Gladstone and Stanford researchers had to look for other genes that could be hijacked to reduce those toxic levels. One such gene, Dbr1, makes an enzyme that normally breaks down RNAs. The research teams found that if they lowered Dbr1 levels, the RNAs could not be broken down. These unprocessed RNAs could then serve as "bait" to bind to TDP-43, storing it away safely—and presumably allowing the RNAs that maintain healthy neurons to continue to function normally.

In laboratory experiments, Dr. Farese and Gladstone Postdoctoral Fellow Matthew Higgins, PhD, first showed that yeast makes an excellent model for studying ALS. Many RNA-processing genes in yeast resemble those found in humans—including Dbr1. At the same time, Dr. Gitler's lab found that Dbr1 suppressed TDP-43 toxicity in yeast models. So, the Farese and Gitler laboratories compared these findings to those from rat neurons analyzed Dr. Finkbeiner's lab.

"Even though millions of years of evolution separate yeast and rats, we found the same results in both models," said Dr. Higgins, one of the study's lead authors. "Our combined analyses revealed that the leftover RNAs acted as a decoy—tricking TDP-43 into binding them rather than the RNAs that are crucial for cell survival. The cells remained healthy."

The findings—while preliminary—could have far-reaching implications, as they may be relevant also to other conditions besides ALS. For example, TDP-43 toxicity has also been observed in frontotemporal dementia (FTD), a form of early-onset dementia that causes progressive memory loss. However, questions remain before Dbr1 can be harnessed to treat patients.

"We don't yet know how switching off the Dbr1 gene in a living organism will affect the organism's overall health," said Dr. Gitler, who is one of the paper's senior authors. "Our next steps are to extend these studies from yeast and cell culture into live animal models. Then we can begin to identify small molecules that may inhibit Dbr1."

"We are optimistic about what the results of our joint efforts might mean to ALS patients in the future," added Dr. Finkbeiner, who is also a UCSF professor. "People with ALS have lived and died for far too long with no hope of recovery. We believe that these findings could be a step towards changing that."

Explore further: Disease progression halted in rat model of Lou Gehrig's disease

Related Stories

Disease progression halted in rat model of Lou Gehrig's disease

December 12, 2011
Amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig's disease) is an incurable adult neurodegenerative disorder that progresses to paralysis and death. Genetic mutations are the cause of disease in 5% of patients ...

Potential new drug target in Lou Gehrig's disease

November 14, 2011
Two proteins conspire to promote a lethal neurological disease, according to a study published online this week in the Journal of Experimental Medicine.

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, ...

Recommended for you

Gene therapy improves immunity in babies with 'bubble boy' disease

December 9, 2017
Early evidence suggests that gene therapy developed at St. Jude Children's Research Hospital will lead to broad protection for infants with the devastating immune disorder X-linked severe combined immunodeficiency disorder. ...

In lab research, scientists slow progression of a fatal form of muscular dystrophy

December 8, 2017
In a paper published in the Nature journal Scientific Reports, Saint Louis University (SLU) researchers report that a new drug reduces fibrosis (scarring) and prevents loss of muscle function in an animal model of Duchenne ...

Double-blind study shows HIV vaccine not effective in viral suppression

December 7, 2017
(Medical Xpress)—A large team of researchers from the U.S. and Canada has conducted a randomized double-blind study of the effectiveness of an HIV vaccine and has found it to be ineffective in suppressing the virus. In ...

Time matters: Does our biological clock keep cancer at bay?

December 7, 2017
Our body has an internal biological or "circadian" clock, which cycles daily and is synchronized with solar time. New research done in mice suggests that it can help suppress cancer. The study, publishing 7 December in the ...

Novel harvesting method rapidly produces superior stem cells for transplantation

December 7, 2017
A new method of harvesting stem cells for bone marrow transplantation - developed by a team of investigators from the Massachusetts General Hospital (MGH) Cancer Center and the Harvard Stem Cell Institute - appears to accomplish ...

Inhibiting TOR boosts regenerative potential of adult tissues

December 7, 2017
Adult stem cells replenish dying cells and regenerate damaged tissues throughout our lifetime. We lose many of those stem cells, along with their regenerative capacity, as we age. Working in flies and mice, researchers at ...

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

Twin
1 / 5 (1) Oct 28, 2012
I have no doubt that there is no shortage of als sufferers that would be willing to submit to trials no matter the risks. I've had one personal friend die and another currently in a later stage of this terrible affliction.

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.