Featured Research

from universities, journals, and other organizations

Genetic Engineering Cures Mice Of Brain Disorder

Date:
February 12, 2007
Source:
Vanderbilt University Medical Center
Summary:
Researchers at Vanderbilt University Medical Center and Erasmus Medical Center show that preventing the inhibition of CaMKII reverses the neurological deficits in a mouse model of Angelman syndrome, a rare disorder that causes mental retardation, motor impairments and seizures.

Edwin Weeber, Ph.D., and colleagues used a rotarod (pictured here) to test motor coordination in mice with a genetic 'rescue' of Angelman syndrome.
Credit: Photo by Susan Urmy

Children with Angelman syndrome are often seen laughing and smiling, but this cheerful demeanor masks serious neurological problems -- mental retardation, movement problems and seizures.

New research in mice, however, suggests that many of these deficits could be alleviated.

Edwin Weeber, Ph.D., and colleagues reversed the neurological deficits in a mouse model of Angelman syndrome by preventing the inhibition of CaMKII, an enzyme highly expressed in brain regions affected by Angelman syndrome.

The results, which appear in the March issue of Nature Neuroscience (currently available online), reveal an important part of the mechanism underlying the condition and point to potential therapeutic targets for treating these symptoms.

Angelman syndrome, which affects approximately one in 15,000 children, is a debilitating neurological disorder characterized by mental retardation, severely limited speech, and movement and balance problems.

In 1997, researchers determined that Angelman syndrome was caused by a mutation in a single gene, called UBE3A. They subsequently developed a mouse model of Angelman syndrome by mutating this gene.

But the finding was baffling, said Weeber, because UBE3A is a "housekeeping" gene, meaning that it broadly regulates cellular processes not particularly specific for any of the neurological deficits seen in these children. Specifically, the protein encoded by UBE3A "tags" other proteins for degradation by the cellular "garbage disposal," the proteasome.

"The most difficult thing to rationalize was that this housekeeping gene -- which nobody thought did anything -- caused severe mental retardation," said Weeber, an assistant professor of Molecular Physiology and Biophysics and Pharmacology and senior author on the study.

"So we started trying to identify some of the protein's molecular targets."

In the process, Weeber and colleagues identified an abnormality in the Angelman syndrome mouse model -- changes in an enzyme called calcium/calmodulin-dependent protein kinase II (CaMKII), which is important in the cellular processes that underlie learning and memory.

They found that, in Angelman syndrome, CaMKII activity was reduced due to an inhibitory chemical modification (phosphorylation). Because of CaMKII's prominent role in neuronal function, Weeber suspected that this might account for many of the neurological deficits seen in Angelman syndrome children.

Fortuitously, one of Weeber's colleagues -- Ype Elgersma, Ph.D., at Erasmus Medical Center in Rotterdam, Netherlands -- had created a mouse with a mutation that prevented this inhibition of CaMKII.

The researchers decided to breed the Angelman mice with the CaMKII mutant mice to see if counteracting the CaMKII inhibition would alleviate the neurological problems.

The researchers then ran the resulting "double mutants" through a battery of neurological and cognitive tests.

Angelman mice performed poorly on learning and memory tasks and displayed impaired motor coordination.

The double mutants, however, showed normal learning and memory and motor coordination. And while the Angelman mice were also prone to seizures, the double mutants showed very low seizure susceptibility.

Weeber was surprised by the robust results. "We thought we might rescue some of the deficits that we saw in the mouse model," he said. "We had no idea that we were going to rescue basically everything."

Although impossible to apply the genetic engineering used in the current study to correct these deficits in mice to humans, Weeber thinks that the findings may point to new therapeutic targets for the disorder.

"It's very conceivable that if we can figure out what lies between UBE3A and CaMKII -- and if it's a specific path -- then that could be a therapeutic target."

But the results may apply more broadly, Weeber said, to other types of mental retardation syndromes that remained unexplained and untreatable.

"There are a lot of mental retardation syndromes that we still don't understand. Maybe the changes in CaMKII associated with Angelman syndrome could be implicated in other mental retardation syndromes as well."

Weeber is also an investigator in the Vanderbilt Kennedy Center for Research on Human Development.


Story Source:

The above story is based on materials provided by Vanderbilt University Medical Center. Note: Materials may be edited for content and length.


Cite This Page:

Vanderbilt University Medical Center. "Genetic Engineering Cures Mice Of Brain Disorder." ScienceDaily. ScienceDaily, 12 February 2007. <www.sciencedaily.com/releases/2007/02/070210170650.htm>.
Vanderbilt University Medical Center. (2007, February 12). Genetic Engineering Cures Mice Of Brain Disorder. ScienceDaily. Retrieved September 16, 2014 from www.sciencedaily.com/releases/2007/02/070210170650.htm
Vanderbilt University Medical Center. "Genetic Engineering Cures Mice Of Brain Disorder." ScienceDaily. www.sciencedaily.com/releases/2007/02/070210170650.htm (accessed September 16, 2014).

Share This



More Plants & Animals News

Tuesday, September 16, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Some Tobacco Farmers Thrive Amid Challenges

Some Tobacco Farmers Thrive Amid Challenges

AP (Sep. 16, 2014) The South's tobacco country is surviving, and even thriving in some cases, as demand overseas keeps growers in the fields of one of America's oldest cash crops. (Sept. 16) Video provided by AP
Powered by NewsLook.com
Scientists Given Rare Glimpse of 350-Kilo Colossal Squid

Scientists Given Rare Glimpse of 350-Kilo Colossal Squid

AFP (Sep. 16, 2014) Scientists say a female colossal squid weighing an estimated 350 kilograms (770 lbs) and thought to be only the second intact specimen ever found was carrying eggs when discovered in the Antarctic. Duration: 00:47 Video provided by AFP
Powered by NewsLook.com
Raw: Scientists Examine Colossal Squid

Raw: Scientists Examine Colossal Squid

AP (Sep. 16, 2014) Squid experts in New Zealand thawed and examined an unusual catch on Tuesday: a colossal squid. It was captured in Antarctica's remote Ross Sea in December last year and has been frozen for eight months. (Sept. 16) Video provided by AP
Powered by NewsLook.com
Ivorians Abandon Monkey Pets in Fear Over Ebola Virus

Ivorians Abandon Monkey Pets in Fear Over Ebola Virus

AFP (Sep. 16, 2014) Since the arrival of Ebola in Ivory Coast, Ivorians have been abandoning their pets, particularly monkeys, in the fear that they may transmit the virus. Duration: 00:47 Video provided by AFP
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