Featured Research

from universities, journals, and other organizations

Why Repair Of Brain's Wiring Fails

Date:
August 24, 2009
Source:
University of California - San Francisco
Summary:
Scientists have uncovered new evidence suggesting that damage to nerve cells in people with multiple sclerosis accumulates because the body's natural mechanism for repair of the nerve coating called "myelin" stalls out.

Scientists have uncovered new evidence suggesting that damage to nerve cells in people with multiple sclerosis accumulates because the body's natural mechanism for repair of the nerve coating called "myelin" stalls out.

The study, published July 1, 2009, in the print edition of Genes & Development, was conducted by scientists at the University of California, San Francisco and University of Cambridge. The research was led by co-senior investigator David Rowitch, MD, PhD, a Howard Hughes Medical Institute investigator at UCSF.

The investigation, conducted in mice and in human tissue, showed that repair of nerve fibers is hampered by biochemical signals that inhibit the development of cells known as oligodendrocytes, which function as repair workers in the brain.

Oligodendrocytes form a protective sheath, known as myelin, that insulates the fibrous cables, or axons, radiating from nerve cells. In multiple sclerosis, the immune system's T cells and B cells attack oligodendrocytes, ultimately damaging the myelin sheath to the point that the electrical signals transmitted by the axons beneath it are disrupted.

Remarkably, the brain generally is able to recruit fresh, immature oligodendrocytes to the myelin sheath to repair the damage, for a time. This explains why, in the most common form of the disease, known as relapsing remitting MS, the symptoms -- which range from tingling and numbness in the limbs to loss of vision and paralysis -- disappear or are greatly reduced, for some times months or years at a time.

Ultimately, however, the repair process falters and the disease progresses. In their study, the team set out to see if they could determine what was slowing down myelin repair. They lesioned a small region of white matter in healthy mice, then monitored the repair process, examining the tissue after five, 10, and 14 days.

To find out which genes were contributing to three key stages in the repair process – the recruitment of oligodendrocyte precursors to the site of injury, the maturation of those cells into functional oligodendrocytes, and the formation of a new myelin sheath -- they measured the activity of 1,040 genes. All of the genes they studied encode transcription factors, which regulate the activity of other genes. Their experiments showed that 50 transcription factors are working during key steps in myelin repair.

The team then honed in on a gene called Tcf4, because its expression was strong in damaged areas where repair attempts were under way.

Tcf4 is involved in a cascade of biochemical events known as the Wnt (pronounced "wint") pathway, whose importance has been well recognized in normal development of many tissues, including the brain. Until now, however, Wnt had not been linked to myelin production or repair.

"This is the first evidence implicating the Wnt pathway in multiple sclerosis," says lead author Stephen P.J. Fancy, PhD, a postdoctoral fellow in the Rowitch lab. "We consider this an exciting development in our efforts to understand why the repair process often fails in the disease."

To glean further evidence about Wnt's role, the researchers hyperactivated the Wnt pathway in the oligodendrocytes of mice, which caused a profound delay in repair. Further analysis suggested that the Wnt pathway activation was creating a roadblock that prolonged oligodendrocyte precursor development.

"While the animals eventually showed repair, it was delayed compared to normal mice," says Fancy. The researchers also tested human tissue for the presence of Tcf4, and found the protein in areas damaged by MS but not in healthy white matter. Further, the researchers examined available data from another study and found that many signaling molecules of the Wnt pathway are overactive in lesions of patients with MS.

"This is an important step that we hope will lead to targeted therapies involving the repair process," says co-senior author Robin Franklin of the University of Cambridge.

Now the team is starting to examine some of the other genes it found to be active in the myelin repair process, and is developing new mouse models to help test potential therapies that might manipulate the Wnt pathway to improve myelin repair. Given the pathway's role in so many different processes, however, Rowitch cautioned that targeting Wnt could cause unintended side effects.

The new work may also have implications for another neurological disease, periventricular leukomalacia, which can lead to cerebral palsy in extremely premature infants, says Rowitch. Recent studies by Rowitch and colleagues show a similar inability of oligodendrocytes to perform their important repair function.

"The researchers have made an encouraging finding that could open a new window into the cause of failed neural repair in multiple sclerosis," says Dr. Patricia O'Looney, Vice President of BioMedical Research at the National Multiple Sclerosis Society. "Understanding such mechanisms should help advance the efforts to find valuable treatments for this debilitating disease."

The work was funded by the National Multiple Sclerosis Society, the United Kingdom Multiple Sclerosis Society and the National Institutes of Health and Howard Hughes Medical Institute.

Co-authors of the study were Sergio E. Baranzini, Karen-Amanda Irvine and Nader Sanai, of UCSF, Chao Zhao of University of Cambridge and Dong-In Yuk of Dana-Farber Cancer Institute.


Story Source:

The above story is based on materials provided by University of California - San Francisco. Note: Materials may be edited for content and length.


Cite This Page:

University of California - San Francisco. "Why Repair Of Brain's Wiring Fails." ScienceDaily. ScienceDaily, 24 August 2009. <www.sciencedaily.com/releases/2009/07/090701102908.htm>.
University of California - San Francisco. (2009, August 24). Why Repair Of Brain's Wiring Fails. ScienceDaily. Retrieved August 28, 2014 from www.sciencedaily.com/releases/2009/07/090701102908.htm
University of California - San Francisco. "Why Repair Of Brain's Wiring Fails." ScienceDaily. www.sciencedaily.com/releases/2009/07/090701102908.htm (accessed August 28, 2014).

Share This




More Health & Medicine News

Thursday, August 28, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Mini Pacemaker Has No Wires

Mini Pacemaker Has No Wires

Ivanhoe (Aug. 27, 2014) Cardiac experts are testing a new experimental device designed to eliminate major surgery and still keep the heart on track. Video provided by Ivanhoe
Powered by NewsLook.com
After Cancer: Rebuilding Breasts With Fat

After Cancer: Rebuilding Breasts With Fat

Ivanhoe (Aug. 27, 2014) More than 269 million women are diagnosed with breast cancer each year. Many of them will need surgery and radiation, but there’s a new simple way to reconstruct tissue using a patient’s own fat. Video provided by Ivanhoe
Powered by NewsLook.com
Blood Clots in Kids

Blood Clots in Kids

Ivanhoe (Aug. 27, 2014) Every year, up to 200,000 Americans die from a blood clot that travels to their lungs. You’ve heard about clots in adults, but new research shows kids can get them too. Video provided by Ivanhoe
Powered by NewsLook.com
Radio Waves Knock out Knee Pain

Radio Waves Knock out Knee Pain

Ivanhoe (Aug. 27, 2014) Doctors have used radio frequency ablation or RFA to reduce neck and back pain for years. But now, that same technique is providing longer-term relief for patients with severe knee pain. Video provided by Ivanhoe
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