Featured Research

from universities, journals, and other organizations

Key to controlling toxicity of Huntington's disease protein may be cell contents

Date:
June 6, 2012
Source:
Georgia Institute of Technology, Research Communications
Summary:
New research proposes novel therapeutic targets for treating Huntington’s disease. A new study found the toxic effects of the huntingtin protein on cells may not be driven exclusively by the length of the protein’s expansion, but also by which other proteins are present in the cell.

Image showing sequestration of the prion form of translation release factor Sup35 (red) by polyglutamines in an aggresome (green).
Credit: Yury Chernoff

New research into the cell-damaging effects of Huntington's disease suggests a potentially new approach for identifying possible therapeutic targets for treating the nerve-destroying disorder.

Huntington's disease causes the progressive breakdown of nerve cells in the brain and affects an individual's movement, cognition and mental state. Genetically, the disease is associated with a mutation in the Huntingtin gene that causes the huntingtin protein to be produced with an extended region containing the amino acid glutamine.

The mechanisms that control the severity and onset of the disease are poorly understood, as individuals with the same amount of expansion in their huntingtin proteins experience differences in toxicity and onset of the disease.

A new study led by Georgia Institute of Technology researchers suggests that the toxic effects of the huntingtin protein on cells may not be driven exclusively by the length of the protein's expansion, but also by which other proteins are present in the cell.

The researchers placed human huntingtin protein with an expanded region, called a polyglutamine tract, into yeast cells and found toxicity differences that were based on the other protein aggregates -- called prions -- present in the cells.

"This study clarifies genetic and epigenetic mechanisms that modulate polyglutamine's toxicity on cells and establishes a new approach for identifying potential therapeutic targets through characterization of pre-existing proteins in the cell," said Yury Chernoff, a professor in the School of Biology at Georgia Tech. "While this study was conducted in yeast, it is possible that there are differences in aggregated proteins present in human cells as well, which are causing variation in huntingtin toxicity among individuals."

The results of the study were published in the April 2012 issue of the journal PLoS Genetics. This work was supported by the National Institutes of Health and the Hereditary Disease Foundation.

Also contributing to this research were former Georgia Tech graduate student He Gong and postdoctoral fellow Nina Romanova, University of North Carolina at Chapel Hill School of Medicine research assistant professor Piotr Mieczkowski, and Boston University School of Medicine professor Michael Sherman.

Expanded huntingtin forms clumps in human cells that are typically transported and stored in an internal compartment called an aggresome until they can be removed from the body. While the compartment is thought to protect the contents of the cell from the toxic contents inside the aggresome, the current study shows that huntingtin molecules inside an aggresome can still be toxic to the cell.

In the study, aggresome formation in the cells containing the prion form of the Rnq1 protein reduced the toxicity of the huntingtin protein in Saccharomyces cerevisiae yeast cells, whereas the huntingtin protein's toxicity remained in the presence of the prion form of translation release factor Sup35.

"It remains uncertain whether the toxicity was primarily driven by sequestration of Sup35 into the aggresome or by its sequestration into the smaller huntingtin protein aggregates that remained in the cytoplasm," explained Chernoff, who is also director of the Center for Nanobiology of the Macromolecular Assembly Disorders (NanoMAD). "While Sup35 was detected in the aggresome, we don't know if the functional fraction of Sup35 was sequestered there."

In a follow-on experiment, the researchers increased the level of another release factor, Sup45, in the presence of Sup35 and found that this combination counteracted the toxicity.

"While the Rnq1 and Sup35 prions did not cause significant toxicity on their own, the results show that prion composition in the cell drove toxicity," noted Chernoff. "Prions modulated which proteins were sequestered by the aggresome, as proteins associated with the pre-existing prions were more likely to be sequestered, such as Sup45 because of its association with Sup35."

It remains unknown if polyglutamines can sequester the human versions of the Sup35 and Sup45 release factors, but this study shows the possibility that organisms may differ by the protein composition in their cells, and this in turn may influence their susceptibility to polyglutamine disorders such as Huntington's disease.


Story Source:

The above story is based on materials provided by Georgia Institute of Technology, Research Communications. The original article was written by Abby Robinson. Note: Materials may be edited for content and length.


Journal Reference:

  1. He Gong, Nina V. Romanova, Kim D. Allen, Pavithra Chandramowlishwaran, Kavita Gokhale, Gary P. Newnam, Piotr Mieczkowski, Michael Y. Sherman, Yury O. Chernoff. Polyglutamine Toxicity Is Controlled by Prion Composition and Gene Dosage in Yeast. PLoS Genetics, 2012; 8 (4): e1002634 DOI: 10.1371/journal.pgen.1002634

Cite This Page:

Georgia Institute of Technology, Research Communications. "Key to controlling toxicity of Huntington's disease protein may be cell contents." ScienceDaily. ScienceDaily, 6 June 2012. <www.sciencedaily.com/releases/2012/06/120606092537.htm>.
Georgia Institute of Technology, Research Communications. (2012, June 6). Key to controlling toxicity of Huntington's disease protein may be cell contents. ScienceDaily. Retrieved September 1, 2014 from www.sciencedaily.com/releases/2012/06/120606092537.htm
Georgia Institute of Technology, Research Communications. "Key to controlling toxicity of Huntington's disease protein may be cell contents." ScienceDaily. www.sciencedaily.com/releases/2012/06/120606092537.htm (accessed September 1, 2014).

Share This




More Health & Medicine News

Monday, September 1, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

We've Got Mites Living In Our Faces And So Do You

We've Got Mites Living In Our Faces And So Do You

Newsy (Aug. 30, 2014) A new study suggests 100 percent of adult humans (those over 18 years of age) have Demodex mites living in their faces. Video provided by Newsy
Powered by NewsLook.com
Liberia Continues Fight Against Ebola

Liberia Continues Fight Against Ebola

AFP (Aug. 30, 2014) Authorities in Liberia try to stem the spread of the Ebola epidemic by raising awareness and setting up sanitation units for people to wash their hands. Duration: 00:41 Video provided by AFP
Powered by NewsLook.com
California Passes 'yes-Means-Yes' Campus Sexual Assault Bill

California Passes 'yes-Means-Yes' Campus Sexual Assault Bill

Reuters - US Online Video (Aug. 30, 2014) California lawmakers pass a bill requiring universities to adopt "affirmative consent" language in their definitions of consensual sex, part of a nationwide drive to curb sexual assault on campuses. Linda So reports. Video provided by Reuters
Powered by NewsLook.com
New Drug Could Reduce Cardiovascular Deaths

New Drug Could Reduce Cardiovascular Deaths

Newsy (Aug. 30, 2014) The new drug from Novartis could reduce cardiovascular deaths by 20 percent compared to other similar drugs. 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:
from the past week

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