Featured Research

from universities, journals, and other organizations

Hopkins Scientists Discover How Huntington's Kills Cells: Block Death In Cultures

Date:
March 23, 2001
Source:
Johns Hopkins Medical Institutions
Summary:
Scientists discovered the gene for Huntington’s disease in 1993, but in all that time, they couldn’t explain how the gene leads to the death of a small patch of nerve cells in a key part of the brain. Now studies from two laboratories at Johns Hopkins suggest precisely what goes awry in the brain cells marked for destruction: a mutant protein "hijacks" a key molecule in a cell’s survival system.

Scientists discovered the gene for Huntington’s disease in 1993, but in all that time, they couldn’t explain how the gene leads to the death of a small patch of nerve cells in a key part of the brain.

Related Articles


Now studies from two laboratories at Johns Hopkins suggest precisely what goes awry in the brain cells marked for destruction: a mutant protein "hijacks" a key molecule in a cell’s survival system. Using what they’ve learned, the researchers have also been able to fully reverse impending cell death in laboratory cultures of human cells containing the mutant HD gene.

An account of the study appears this week in the journal Science.

"Obviously, our goal has been to understand HD’s mechanism so we can interfere with it early on with drugs," says lead researcher Christopher A. Ross, M.D., Ph.D. "But this is also a broader advance," says neuroscientist Ted M. Dawson, M.D., Ph.D. "It shows us a new way in which genetic errors could cause disease."

Huntington’s disease is a fatal hereditary disorder, marked by death of nerve cells chiefly in the corpus striatum, a part of the brain that helps control movement and thought. Patients need inherit only a single mutant gene to get HD. Symptoms typically begin in middle age, usually as uncontrollable movement followed by progressive dementia and death.

"We’ve long known that the abnormal gene produces a flawed form of a protein called huntingtin," says Ross. Like a train with too many dining cars, the irregular molecule has too many repeats of glutamine, one of its amino acid subunits. Brain cells of patients with HD show characteristic clumping of the flawed huntingtin.

But the clumped molecule itself apparently isn’t harmful. "The real problem is that the abnormally shaped protein attracts and becomes entangled with a smaller, critical protein in the cell nucleus," says doctoral student Frederick C. Nucifora, Jr. The smaller protein — a regulatory molecule called CBP — gets "pulled away" from its place of action alongside DNA and then becomes entangled and useless, says Ross.

"Without CBP," he continues, "a pathway crucial for cell survival never gets turned on."

To prove CPB gets hijacked, the researchers attached different colored fluorescent markers to DNA, huntingtin and CBP and watched what happened inside cells to which they’d added mutant HD genes. They could see the CBP get sequestered out of the nucleus. They also showed this "hijacking" in live mice carrying the human HD gene and in postmortem brains from human HD patients.

Assays of gene activity in the nerve cells showed that, under these conditions, CBP’s normal gene-regulating activity — turning on genes for survival pathways — wasn’t happening.

But most striking, the researchers say, was being able to reverse the process in the test tube, turning around the cells’ slide into death.

In earlier studies, when researchers in Ross’s lab inserted mutant HD genes into nerve cells in culture, the cells died in a way identical to brain cells of HD patients. But this time, when the scientists introduced mutant HD genes into cultured cells, they also added a bogus version of CBP with the molecular areas normally attracted to mutant huntingtin snipped out.

Now, unable to be hijacked, the engineered CBP could perform its survival task. "Instead of degenerating," Ross says, "cells in these cultures remained healthy. We were able to rescue them completely."

"We haven’t yet demonstrated the turnaround in a live mouse model," says Ross. That’s a critical step, both in proving the principle and taking a future road to human therapy. The researchers anticipate technical details will complicate this work "Our research so far, however, offers a needed target for developing and testing new drugs."

The results of the study also apply to a growing family of neurological genetic diseases which, the researchers say, operate on a similar principle. They include the spinocerebellar ataxias, a set of rare but debilitating diseases of movement and gait.

The research was funded by grants from the Huntington’s Disease Society of America, the Hereditary Disease Foundation and the National Institute of Neurological Disorders and Stroke.

Other researchers on the team are: Masayuki Sasaki, Ph.D., Mathew F. Peters, Ph.D., Hui Huang, Jillian K. Cooper, Ph.D., Juan Troncoso, M.D., and Valina Dawson, Ph.D., from Johns Hopkins. Hitoshi Takahashi, Mitsunori Yamada and Shoji Tsuji from Niigata University in Japan also participated.

Check this Web site to see photographs from the study: http://hopkins.med.jhu.edu/press/2001/MARCH/010322A.HTM

Other related Web sites:

Dr. Ross’s research Web site: http://www.med.jhu.edu/neurosci/web_text_neurosci-PRIMARY-ROSS.html

This is Dr. Dawson’s Web site: http://www.med.jhu.edu/neurosci/web_text_neurosci_PRIMARY_T_DAWSON.html

For links to the Huntington’s Disease Society of America: http://www.hdsa.org/

Another lay-oriented site: http://www.interlog.com/~rlaycock/what.html


Story Source:

The above story is based on materials provided by Johns Hopkins Medical Institutions. Note: Materials may be edited for content and length.


Cite This Page:

Johns Hopkins Medical Institutions. "Hopkins Scientists Discover How Huntington's Kills Cells: Block Death In Cultures." ScienceDaily. ScienceDaily, 23 March 2001. <www.sciencedaily.com/releases/2001/03/010322232740.htm>.
Johns Hopkins Medical Institutions. (2001, March 23). Hopkins Scientists Discover How Huntington's Kills Cells: Block Death In Cultures. ScienceDaily. Retrieved October 24, 2014 from www.sciencedaily.com/releases/2001/03/010322232740.htm
Johns Hopkins Medical Institutions. "Hopkins Scientists Discover How Huntington's Kills Cells: Block Death In Cultures." ScienceDaily. www.sciencedaily.com/releases/2001/03/010322232740.htm (accessed October 24, 2014).

Share This



More Mind & Brain News

Friday, October 24, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Academic Scandal Shocks UNC

Academic Scandal Shocks UNC

AP (Oct. 23, 2014) A scandal involving bogus classes and inflated grades at the University of North Carolina was bigger than previously reported, a new investigation found. (Oct. 23) Video provided by AP
Powered by NewsLook.com
Working Mother Getaway: Beaches Turks & Caicos

Working Mother Getaway: Beaches Turks & Caicos

Working Mother (Oct. 22, 2014) Feast your eyes on this gorgeous family-friendly resort. Video provided by Working Mother
Powered by NewsLook.com
What Your Favorite Color Says About You

What Your Favorite Color Says About You

Buzz60 (Oct. 22, 2014) We all have one color we love to wear, and believe it or not, your color preference may reveal some of your character traits. In celebration of National Color Day, Krystin Goodwin (@kyrstingoodwin) highlights what your favorite colors may say about you. Video provided by Buzz60
Powered by NewsLook.com
First-Of-Its-Kind Treatment Gives Man Ability To Walk Again

First-Of-Its-Kind Treatment Gives Man Ability To Walk Again

Newsy (Oct. 21, 2014) A medical team has for the first time given a man the ability to walk again after transplanting cells from his brain onto his severed spinal cord. 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