Featured Research

from universities, journals, and other organizations

Subtle change dramatically reduces pathogenic potential of Huntington's protein

Date:
December 23, 2009
Source:
Cell Press
Summary:
Scientists have identified a key molecular switch that may drive the onset of Huntington's disease (HD), an incurable neurodegenerative disorder that leads to severe disruptions in muscle coordination and cognitive function. The research enhances the understanding of HD pathogenesis and may direct new strategies for treating this devastating brain disease.

Scientists have identified a key molecular switch that may drive the onset of Huntington's disease (HD), an incurable neurodegenerative disorder that leads to severe disruptions in muscle coordination and cognitive function. The research, published in the December 24 issue of the journal Neuron, enhances the understanding of HD pathogenesis and may direct new strategies for treating this devastating brain disease.

HD is caused by an abnormally lengthy repeating stretch of the amino acid glutamine within a large protein called huntingtin (htt). Huntingtin is thought to function as a kind of molecular scaffold that mediates many intricate cellular processes. "It's unclear how the mutant protein causes age-related and progressive loss of brain cells in patients with Huntington's disease," explains senior study author X. William Yang, M.D., Ph.D., of the Jane and Terry Semel Institute of Neuroscience and Human Behavior at David Geffen School of Medicine at UCLA. "Our study explored whether regions of the protein besides the polyglutamine mutation play a role in the development of the disorder."

Recent work has revealed that two specific amino acids in htt, serine 13 (S13) and serine 16 (S16), can be phosphorylated. Phosphorylation is a relatively common signaling mechanism that enables proteins to be regulated via attachment of phosphate groups to specific amino acids. To investigate the importance of phosphorylation to disease pathogenesis in a mouse model of HD, Dr. Yang and colleagues introduced mutations that elicited or prevented phosphorylation of full-length mutant htt (mhtt). Specifically, they replaced the S13 and S16 with phosphomimetic aspartate (SD) or phosphoresistant alanine (SA).

The researchers found that full-length mhtt induced motor and psychiatric-like behavioral deficits, mhtt aggregation, and selective neurodegeneration in the SA mice but that these pathological changes were absent in the SD mice. In addition, SD mutations had a dramatic impact on the process of mhtt protein aggregation while SA mutations did not. Taken together, the findings demonstrate that subtle molecular changes of only two amino acids in full-length mhtt dramatically reduced the pathogenic potential of the mutant protein.

"It is now crucial to understand how subtle modifications in this critical molecular switch can have such a profound impact on disease pathogenesis," said Yang. "It is also important to screen for drugs that can enhance or mimic the effects of phosphorylation which may help to detoxify the mutant huntingtin protein and prevent the onset of HD."

The researchers include Xiaofeng Gu, University of California, Los Angeles, Los Angeles, CA; Erin R. Greiner, University of California, Los Angeles, Los Angeles, CA; Rakesh Mishra, University of Pittsburgh School of Medicine, Pittsburgh, PA; Ravindra Kodali, University of Pittsburgh School of Medicine, Pittsburgh, PA; Alex Osmand, University of Tennessee Graduate School of Medicine, Knoxville, TN; Steven Finkbeiner, University of California, San Francisco, San Francisco, CA; Joan S. Steffan, University of California, Irvine, Irvine, CA; Leslie Michels Thompson, University of California, Irvine, Irvine, CA; Ronald Wetzel, University of Pittsburgh School of Medicine, Pittsburgh, PA; and X. William Yang, University of California, Los Angeles, Los Angeles, CA.


Story Source:

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


Cite This Page:

Cell Press. "Subtle change dramatically reduces pathogenic potential of Huntington's protein." ScienceDaily. ScienceDaily, 23 December 2009. <www.sciencedaily.com/releases/2009/12/091223125123.htm>.
Cell Press. (2009, December 23). Subtle change dramatically reduces pathogenic potential of Huntington's protein. ScienceDaily. Retrieved July 28, 2014 from www.sciencedaily.com/releases/2009/12/091223125123.htm
Cell Press. "Subtle change dramatically reduces pathogenic potential of Huntington's protein." ScienceDaily. www.sciencedaily.com/releases/2009/12/091223125123.htm (accessed July 28, 2014).

Share This




More Mind & Brain News

Monday, July 28, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Losing Sleep Leaves You Vulnerable To 'False Memories'

Losing Sleep Leaves You Vulnerable To 'False Memories'

Newsy (July 27, 2014) A new study shows sleep deprivation can make it harder for people to remember specific details of an event. Video provided by Newsy
Powered by NewsLook.com
University Quiz Implies Atheists Are Smarter Than Christians

University Quiz Implies Atheists Are Smarter Than Christians

Newsy (July 25, 2014) An online quiz from a required course at Ohio State is making waves for suggesting atheists are inherently smarter than Christians. Video provided by Newsy
Powered by NewsLook.com
Beatings and Addiction: Pakistan Drug 'clinic' Tortures Patients

Beatings and Addiction: Pakistan Drug 'clinic' Tortures Patients

AFP (July 24, 2014) A so-called drugs rehab 'clinic' is closed down in Pakistan after police find scores of ‘patients’ chained up alleging serial abuse. Duration 03:05 Video provided by AFP
Powered by NewsLook.com
New Painkiller Designed To Discourage Abuse: Will It Work?

New Painkiller Designed To Discourage Abuse: Will It Work?

Newsy (July 24, 2014) The FDA approved Targiniq ER on Wednesday, a painkiller designed to keep users from abusing it. Like any new medication, however, it has doubters. 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