Featured Research

from universities, journals, and other organizations

Getting off tract: Polyglutamine disease involves other regions of protein

Date:
September 23, 2010
Source:
Cell Press
Summary:
Many genes code for proteins that have a "polyglutamine tract," several glutamine amino acid residues in a row. Nine inherited neurodegenerative diseases, including Huntington's disease and spinocerebellar ataxia type 1 (SCA1), are associated with mutations that cause abnormally long polyglutamine tracts. One theory suggests that accumulation of proteins with extra glutamines damages and kills neurons. However, there is evidence that glutamine tract expansion alone is not sufficient to cause disease.

Many genes code for proteins that have a "polyglutamine tract," several glutamine amino acid residues in a row. Nine inherited neurodegenerative diseases, including Huntington's disease and spinocerebellar ataxia type 1 (SCA1), are associated with mutations that cause abnormally long polyglutamine tracts. One theory suggests that accumulation of proteins with extra glutamines damages and kills neurons. However, there is evidence that glutamine tract expansion alone is not sufficient to cause disease.

Now, new research published by Cell Press in the September 23 issue of the journal Neuron, reveals that initiation and progression of SCA1 are distinct from cell death and that changes outside of the polyglutamine tract are critical for disease pathogenesis. These findings could help to direct future therapeutic strategies for treating polyglutamine diseases.

SCA1 is thought to be caused by an expanded polyglutamine tract in an ataxin (ATXN1) protein that leads to damage and loss of Purkinje cells in the cerebellum. In addition, phosphorylation of a serine amino acid reside at position 776 (Ser776) is thought to be critical for pathogenesis. Recent research led by Dr. Harry T. Orr from the University of Minnesota showed that replacing Ser776 with a phospho-mimicking aspartic acid residue in ATXN1 with a normal polyglutamine tract seemed to elicit biochemical properties that resembled ATXN1 with an expanded polyglutamine tract.

To investigate the biological relevance of this earlier observation, Dr. Orr's group created transgenic mice that expressed different versions of ATXN1 in cerebellar Purkinje cells. "We found that a single amino acid change -- one that mimics phosphorylation at residue 776 -- converts wild type protein in a disease-causing protein. Clearly, phosphorylation is critical for this disease," explains Dr. Orr. The researchers went on to show that although the amino acid substitution caused the normal version of the protein to induce disease in cerebellar neurons, the pathogenesis did not progress to cell death.

Taken together, these results suggest that Ser776 is critical for initiating neuronal dysfunction, while an expanded polyglutamine tract is essential for neuronal death. "Obviously, the two are linked in that initiation is a prerequisite of later stages. Regardless, a treatment targeted at initiation, perhaps S776 phosphorylation, is likely to have a major impact clinically. Conversely treating just the cell death phase of the disease is unlikely to improve the neurological status of patients," concludes Dr. Orr.

The researchers include Lisa Duvick, University of Minnesota, Minneapolis, MN; Justin Barnes, University of Minnesota, Minneapolis, MN; Blake Ebner, University of Minnesota, Minneapolis, MN; Smita Agrawal, University of Minnesota, Minneapolis, MN; Michael Andresen, University of Minnesota, Minneapolis, MN; Janghoo Lim, Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX; Glenn J. Giesler, University of Minnesota, Minneapolis, MN; Huda Y. Zoghbi, Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX; and Harry T. Orr, University of Minnesota, Minneapolis, MN.


Story Source:

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


Journal Reference:

  1. Lisa Duvick, Justin Barnes, Blake Ebner, Smita Agrawal, Michael Andresen, Janghoo Lim, Glenn J. Giesler, Huda Y. Zoghbi, Harry T. Orr. SCA1-like Disease in Mice Expressing Wild-Type Ataxin-1 with a Serine to Aspartic Acid Replacement at Residue 776. Neuron, 2010; 67 (6): 929-935 DOI: 10.1016/j.neuron.2010.08.022

Cite This Page:

Cell Press. "Getting off tract: Polyglutamine disease involves other regions of protein." ScienceDaily. ScienceDaily, 23 September 2010. <www.sciencedaily.com/releases/2010/09/100922121941.htm>.
Cell Press. (2010, September 23). Getting off tract: Polyglutamine disease involves other regions of protein. ScienceDaily. Retrieved October 20, 2014 from www.sciencedaily.com/releases/2010/09/100922121941.htm
Cell Press. "Getting off tract: Polyglutamine disease involves other regions of protein." ScienceDaily. www.sciencedaily.com/releases/2010/09/100922121941.htm (accessed October 20, 2014).

Share This



More Mind & Brain News

Monday, October 20, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Court Ruling Means Kids' Online Activity Could Be On Parents

Court Ruling Means Kids' Online Activity Could Be On Parents

Newsy (Oct. 17, 2014) In a ruling attorneys for both sides agreed was a first of its kind, a Georgia appeals court said parents can be held liable for what kids put online. Video provided by Newsy
Powered by NewsLook.com
The Best Foods To Boost Your Mood

The Best Foods To Boost Your Mood

Buzz60 (Oct. 17, 2014) Feeling down? Reach for the refrigerator, not the medicine cabinet! TC Newman (@PurpleTCNewman) shares some of the best foods to boost your mood. Video provided by Buzz60
Powered by NewsLook.com
You Can Get Addicted To Google Glass, Apparently

You Can Get Addicted To Google Glass, Apparently

Newsy (Oct. 15, 2014) Researchers claim they’ve diagnosed the first example of the disorder in a 31-year-old U.S. Navy serviceman. Video provided by Newsy
Powered by NewsLook.com
First Confirmed Case Of Google Glass Addiction

First Confirmed Case Of Google Glass Addiction

Buzz60 (Oct. 15, 2014) A Google Glass user was treated for Internet Addiction Disorder caused from overuse of the device. Morgan Manousos (@MorganManousos) has the details on how many hours he spent wearing the glasses, and what his symptoms were. Video provided by Buzz60
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