Featured Research

from universities, journals, and other organizations

Loss of key protein boosts neuron loss in amyotrophic lateral sclerosis

Date:
March 7, 2011
Source:
University of California - San Diego
Summary:
Amyotrophic lateral sclerosis, known as ALS or Lou Gehrig's disease, is a notorious neurodegenerative condition characterized by the progressive deterioration of brain and spinal cord neurons, resulting in the gradual but catastrophic loss of muscle control and ultimately, death. Scientists can now describe the profound and pervasive role of a key protein in ALS pathology called TDP-43.

Amyotrophic lateral sclerosis, known as ALS or more popularly, Lou Gehrig's disease, is a notorious neurodegenerative condition characterized by the progressive deterioration of brain and spinal cord neurons, resulting in the gradual but catastrophic loss of muscle control and ultimately, death.

Related Articles


In a new paper, published in the Feb. 27 advance online edition of the journal Nature Neuroscience, a team of scientists at the University of California, San Diego School of Medicine and colleagues describe the profound and pervasive role of a key protein in ALS pathology called TDP-43.

The work was led by Don W. Cleveland, PhD, professor and chair of the UCSD Department of Cellular and Molecular Medicine and head of the Laboratory of Cell Biology at the Ludwig Institute for Cancer Research and Gene Yeo, PhD, assistant professor in the Department of Cellular and Molecular Medicine.

In normal cells, TDP-43 is found in the nucleus where it helps maintain proper levels of ribonucleic acid (RNA), intermediate molecules that translate genetic information from DNA to proteins -- the building blocks of cells.

In the majority of ALS patients, however, TDP-43 accumulates in the cell's cytoplasm -- the liquid that separates the nucleus from the outer membrane, and thus is excluded from the nucleus, which prevents it from performing its normal duties.

Using a mouse model, the researchers made three new important findings:

First, employing a comprehensive genome-wide RNA-binding mapping strategy, they discovered that more than one-third of the genes in the mouse brain are direct targets of TDP-43. In other words, the roles and functions of these genes are impacted by the presence -- or absence -- of normal TDP-43.

Second, the genes most affected had numerous TDP-43 binding sites on very long introns. Introns are the non-coding portions of a gene that are not used to make proteins. Typically, introns are removed (spliced out) during the development of mature messenger RNA. Introns, however, contain binding sites for RNA binding proteins such as TDP-43, to regulate the splicing process.

"This is an important finding as genes expressed in the central nervous system have much longer introns than genes expressed in any other tissues," said Yeo. "This may explain the neuronal selectivity of the disease, and why other types of cells aren't affected."

Third, TDP-43 affects the alternative splicing of many genes. In fact, it affects the alternative splicing of its own RNA message. Said Yeo: "This autoregulation keeps TDP-43 protein levels in check. The loss of TDP-43 removes this check; more TDP-43 is generated and more is likely to accumulate in the cytoplasm."

The deep and expansive impact of misaggregated TDP-43 and the concurrent loss of normal TDP-43 appear to extend beyond ALS. The protein is a central component in the pathogenesis of an ever-increasing list of neurodegenerative conditions. For example, accumulating abnormal TDP-43 in neuronal cytoplasm has been documented in frontotemporal lobar dementia, a neurological disorder that results in progressive changes in personality, the ability to concentrate, social skills, motivation and reasoning.

"It is likely that TDP-43 affects many other neurodegenerative diseases," said Yeo. "Our RNA targets probably reveal the set of genes important for maintaining the normal homeostasis of neurons."

Yeo said the team will now explore which TDP-43 binding sites are critical to how ALS begins and progresses. Ultimately, he said, the information could be used to design new drugs and therapies.

Co-authors of the paper include Magdalini Polymenidou, Clotilde Lagier-Tourenne, Jacqueline Moran, Shuo-Chien Ling, Eveline Sun, Ludwig and Holly Kordasiewicz, Ludwig Institute for Cancer Research at UCSD and the UCSD Department of Cellular and Molecular Medicine; Kasey R. Hutt, Stephanie C. Huelga and Tiffany Y. Liang, UCSD Department of Cellular and Molecular Medicine and UCSD Stem Cell Program and Institute for Genomic Medicine; Edward Wancewicz, Curt Mazur, Yalda Sedaghat and C. Frank Bennett, Isis Pharmaceuticals, Carlsbad, Ca.; John Paul Donohue and Lily Shiue, RNA Center, Department of Molecular, Cell and Developmental Biology, Sinsheimer Labs, UC Santa Cruz.

This work was supported by grants from the National Institutes of Health, the American Recovery and Reinvestment Act and the UCSD Stem Cell Program.


Story Source:

The above story is based on materials provided by University of California - San Diego. The original article was written by Scott LaFee. Note: Materials may be edited for content and length.


Journal Reference:

  1. Magdalini Polymenidou, Clotilde Lagier-Tourenne, Kasey R Hutt, Stephanie C Huelga, Jacqueline Moran, Tiffany Y Liang, Shuo-Chien Ling, Eveline Sun, Edward Wancewicz, Curt Mazur, Holly Kordasiewicz, Yalda Sedaghat, John Paul Donohue, Lily Shiue, C Frank Bennett, Gene W Yeo, Don W Cleveland. Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nature Neuroscience, 2011; DOI: 10.1038/nn.2779

Cite This Page:

University of California - San Diego. "Loss of key protein boosts neuron loss in amyotrophic lateral sclerosis." ScienceDaily. ScienceDaily, 7 March 2011. <www.sciencedaily.com/releases/2011/03/110304151014.htm>.
University of California - San Diego. (2011, March 7). Loss of key protein boosts neuron loss in amyotrophic lateral sclerosis. ScienceDaily. Retrieved November 26, 2014 from www.sciencedaily.com/releases/2011/03/110304151014.htm
University of California - San Diego. "Loss of key protein boosts neuron loss in amyotrophic lateral sclerosis." ScienceDaily. www.sciencedaily.com/releases/2011/03/110304151014.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

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
Madagascar Working to Contain Plague Outbreak

Madagascar Working to Contain Plague Outbreak

AFP (Nov. 24, 2014) — Madagascar said Monday it is trying to contain an outbreak of plague -- similar to the Black Death that swept Medieval Europe -- that has killed 40 people and is spreading to the capital Antananarivo. Duration: 00:42 Video provided by AFP
Powered by NewsLook.com
Are Female Bosses More Likely To Be Depressed?

Are Female Bosses More Likely To Be Depressed?

Newsy (Nov. 24, 2014) — A new study links greater authority with increased depressive symptoms among women in the workplace. 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:

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