Featured Research

from universities, journals, and other organizations

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

Date:
October 28, 2012
Source:
Gladstone Institutes
Summary:
Scientists 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.

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.

Related Articles


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 neurodegenerative diseases such as ALS.

ALS usually strikes between the ages of 40 and 75, ravaging the body's motor neurons -- nerve cells 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 online in Nature Genetics, 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 yeast cells 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 motor neurons 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."


Story Source:

The above story is based on materials provided by Gladstone Institutes. Note: Materials may be edited for content and length.


Journal Reference:

  1. Maria Armakola, Matthew J Higgins, Matthew D Figley, Sami J Barmada, Emily A Scarborough, Zamia Diaz, Xiaodong Fang, James Shorter, Nevan J Krogan, Steven Finkbeiner, Robert V Farese Jr & Aaron D Gitler. Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models. Nature Genetics, 28 October 2012 DOI: 10.1038/ng.2434

Cite This Page:

Gladstone Institutes. "Scientists block toxic protein that plays key role in Lou Gehrig's disease." ScienceDaily. ScienceDaily, 28 October 2012. <www.sciencedaily.com/releases/2012/10/121028141722.htm>.
Gladstone Institutes. (2012, October 28). Scientists block toxic protein that plays key role in Lou Gehrig's disease. ScienceDaily. Retrieved November 26, 2014 from www.sciencedaily.com/releases/2012/10/121028141722.htm
Gladstone Institutes. "Scientists block toxic protein that plays key role in Lou Gehrig's disease." ScienceDaily. www.sciencedaily.com/releases/2012/10/121028141722.htm (accessed November 26, 2014).

Share This


More From ScienceDaily



More Health & Medicine News

Wednesday, November 26, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Pet Dogs to Be Used in Anti-Ageing Trial

Pet Dogs to Be Used in Anti-Ageing Trial

Reuters - Innovations Video Online (Nov. 26, 2014) Researchers in the United States are preparing to discover whether a drug commonly used in human organ transplants can extend the lifespan and health quality of pet dogs. Video provided by Reuters
Powered by NewsLook.com
Today's Prostheses Are More Capable Than Ever

Today's Prostheses Are More Capable Than Ever

Newsy (Nov. 26, 2014) Advances in prosthetics are making replacement body parts stronger and more lifelike than they’ve ever been. Video provided by Newsy
Powered by NewsLook.com
From Popcorn To Vending Snacks: FDA Ups Calorie Count Rules

From Popcorn To Vending Snacks: FDA Ups Calorie Count Rules

Newsy (Nov. 25, 2014) The US FDA is announcing new calorie rules on Tuesday that will require everywhere from theaters to vending machines to include calorie counts. Video provided by Newsy
Powered by NewsLook.com
Daily Serving Of Yogurt Could Reduce Risk Of Type 2 Diabetes

Daily Serving Of Yogurt Could Reduce Risk Of Type 2 Diabetes

Newsy (Nov. 25, 2014) Need another reason to eat yogurt every day? Researchers now say it could reduce a person's risk of developing type 2 diabetes. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:

More Coverage


Yeast Model Offers Clues to Possible Drug Targets for Lou Gehrig's Disease, Study Shows

Oct. 28, 2012 Amyotrophic lateral sclerosis, also called Lou Gehrig's disease, is a devastatingly cruel neurodegenerative disorder that robs sufferers of the ability to move, speak and, finally, breathe. Now ... read more

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins