Featured Research

from universities, journals, and other organizations

Fragile X Syndrome: Fundamental Brain Defect And Probable Drug Target Identified

Date:
September 18, 2007
Source:
Emory University
Summary:
Scientists have discovered how the gene mutation responsible for fragile X syndrome -- the most common inherited form of mental retardation -- alters the way brain cells communicate. In neurons cultured from laboratory rats, the scientists also were able to reverse the effects of the mutation using a drug targeted to the specific site in an upstream pathway of the defect. The finding could lead to the development of human therapies for this previously untreatable condition.

Scientists have discovered how the gene mutation responsible for fragile X syndrome--the most common inherited form of mental retardation--alters the way brain cells communicate. In neurons cultured from laboratory rats, the scientists also were able to reverse the effects of the mutation using a drug targeted to the specific site in an upstream pathway of the defect. The finding could lead to the development of human therapies for this previously untreatable condition.

The research was led by Stephen T. Warren, PhD, Timmie professor and chair of human genetics in Emory University School of Medicine, and Gary J. Bassell, PhD, Emory professor of cell biology. It will be reported in the Proceedings of the National Academy of Sciences the week of Sept. 17. Lead author is Emory genetics postdoctoral fellow Mika Nakamoto.

"We have now explained the fundamental defect in the brain in fragile X syndrome and, most importantly, found that we can correct this problem in the laboratory," says Dr. Warren. "This is quite exciting, progressing from the identification of the gene in 1991 to now believing we will be able to treat a previously untreatable condition. Our next steps will be to continue screening and identifying the best drugs to try and correct the deficiencies that result from fragile X syndrome."

Fragile X syndrome is caused by a mutation in the FMR1 gene on the X chromosome. A region of the mutated FMR1 gene repeats a trinucleotide sequence of DNA bases--CGG--between 200 and 1,000 times, rather than the normal 6 to 55 repeats in normal individuals. The abnormal trinucleotide repeats cause the absence of the FMR protein normally produced by the gene.

Dr. Warren and his colleagues led an international team that discovered the FMR1 gene in 1991. They later characterized the FMR protein (FMRP) and developed diagnostic tests for fragile X syndrome. Ever since, their research has focused on identifying the specific consequences of FMRP deficiency in the brain and finding targets for drug therapy.

Previously, Dr. Warren, working with scientists at Brown University, discovered that the absence of FMRP in the mouse model of fragile X syndrome leads to an abnormality in synaptic strength, or the degree by which neurons communicate, that suggested an abnormality of AMPAR receptors on the surface of neurons.

These receptors are necessary for neurons to connect with each other at synapses, allowing the communication that leads to learning and memory. Drs. Warren and Bassell discovered that in fragile X syndrome, AMPAR receptors move in and out of the surface neuronal cells more frequently and destabilize the synaptic connections. The Emory scientists and others believe this is the ultimate defect in fragile X syndrome.

Using cultured neurons in the laboratory, manipulated to model fragile X syndrome, the Emory scientists were able to target the mGluR5 receptor with an mGluR5 antagonist--MPEP. Since the mGluR5 receptor is upstream of FMRP and has an opposing influence over the neuron, tempering mGluR5 stimulation should normalize the consequence of the loss of FMRP. Indeed, the Emory scientists found the targeted MPEP therapy rescued the abnormal AMPAR receptor movement on the surface of the FMRP-deficient neurons.

"By adding a drug that antagonizes the mGluR5 receptor and signal, we were able to normalize the AMPAR receptor trafficking, and presumably allow the neurons to make appropriate synaptic connections," Dr. Warren says. "This gives us great hope that we will be able to develop treatments for patients with fragile X syndrome."

Fragile X syndrome occurs in approximately 1 in 4,000 males and 1 in 8,000 females. A premutation of the FMR1 gene is present in 1 in 800 males and 1 in 260 females.

Additional Emory authors of the study are Vijayalaxmi Nalavadi, Michael P. Epstein and Usha Narayanan.

The research was supported by the National Institutes of Health and by the Fragile X Research Foundation.


Story Source:

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


Cite This Page:

Emory University. "Fragile X Syndrome: Fundamental Brain Defect And Probable Drug Target Identified." ScienceDaily. ScienceDaily, 18 September 2007. <www.sciencedaily.com/releases/2007/09/070917173149.htm>.
Emory University. (2007, September 18). Fragile X Syndrome: Fundamental Brain Defect And Probable Drug Target Identified. ScienceDaily. Retrieved April 18, 2014 from www.sciencedaily.com/releases/2007/09/070917173149.htm
Emory University. "Fragile X Syndrome: Fundamental Brain Defect And Probable Drug Target Identified." ScienceDaily. www.sciencedaily.com/releases/2007/09/070917173149.htm (accessed April 18, 2014).

Share This



More Health & Medicine News

Friday, April 18, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

'Holy Grail' Of Weight Loss? New Find Could Be It

'Holy Grail' Of Weight Loss? New Find Could Be It

Newsy (Apr. 18, 2014) In a potential breakthrough for future obesity treatments, scientists have used MRI scans to pinpoint brown fat in a living adult for the first time. Video provided by Newsy
Powered by NewsLook.com
Scientists Create Stem Cells From Adult Skin Cells

Scientists Create Stem Cells From Adult Skin Cells

Newsy (Apr. 17, 2014) The breakthrough could mean a cure for some serious diseases and even the possibility of human cloning, but it's all still a way off. Video provided by Newsy
Powered by NewsLook.com
Obama: 8 Million Healthcare Signups

Obama: 8 Million Healthcare Signups

AP (Apr. 17, 2014) President Barack Obama gave a briefing Thursday announcing 8 million people have signed up under the Affordable Care Act. He blasted continued Republican efforts to repeal the law. (April 17) Video provided by AP
Powered by NewsLook.com
Is Apathy A Sign Of A Shrinking Brain?

Is Apathy A Sign Of A Shrinking Brain?

Newsy (Apr. 17, 2014) A recent study links apathetic feelings to a smaller brain. Researchers say the results indicate a need for apathy screening for at-risk seniors. 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