Featured Research

from universities, journals, and other organizations

Rare disease yields clues about broader brain pathology

Date:
November 20, 2013
Source:
University of Wisconsin-Madison
Summary:
Alexander disease is a devastating brain disease that almost nobody has heard of — unless someone in the family is afflicted with it. Alexander disease strikes young or old, and in children destroys white matter in the front of the brain. Many patients, especially those with early onset, have significant intellectual disabilities.

A mutant gene that causes the deadly Alexander disease creates an overgrowth of the protein GFAP in mouse brain cells called astrocytes (right) compared to normal brain cells (left).
Credit: University of Wisconsin-Madison

Alexander disease is a devastating brain disease that almost nobody has heard of -- unless someone in the family is afflicted with it. Alexander disease strikes young or old, and in children destroys white matter in the front of the brain. Many patients, especially those with early onset, have significant intellectual disabilities.

Regardless of the age when it begins, Alexander disease is always fatal. It typically results from mutations in a gene known as GFAP (glial fibrillary acidic protein), leading to the formation of fibrous clumps of protein inside brain cells called astrocytes.

Classically, astrocytes and other glial cells were considered "helpers" that nourish and protect the neurons that do the actual communication. But in recent years, it's become clear that glial cells are much more than passive bystanders, and may be active culprits in many neurological diseases.

Now, in a report in the Journal of Neuroscience, researchers at University of Wisconsin-Madison show that Alexander disease also affects neurons, and in a way that impacts several measures of learning and memory.

Mice were engineered to contain the same mutation in GFAP that is found in human patients. Their astrocytes spontaneously increased production of GFAP, the same response found after many types of injury or disease in the brain. In Alexander disease, the result is an increase in mutant GFAP that is "toxic to the cell, and unfortunately astrocytes respond by making more GFAP," says first author Tracy Hagemann of the university's Waisman Center.

While GFAP is usually found in astrocytes, it also occurs in neural stem cells, a population of cells that persist in some areas of the brain to continually spawn new neurons throughout adulthood. In the mouse versions of Alexander disease, neural stem cells are present, but they fail to develop into neurons, Hagemann says. "Think of a vegetable garden where your green beans never sprouted. Was it too cold for them to sprout, or were they bad seeds? Something similar is happening with these neural stem cells. They are present, but inert, and we're not sure why."

The shortage of new neurons could explain why the mice with excess GFAP failed a test that required them to remember the location of a submerged platform in a tub of water.

The report is "the first to suggest that the problems in Alexander disease extend beyond just the white matter and astrocytes, and may provide a clue to the problems with learning and memory that are such prominent features in the human disease," says lab leader Albee Messing, a professor of comparative biosciences in the UW School of Veterinary Medicine.

One immediate question that the team will try to answer is whether the same defect in stem cells can be found in autopsy samples stored over many years to allow just this kind of investigation.

Still to be clarified is whether the mutation affects the neural stem cells directly, or whether it acts through other astrocytes that are nearby. "We do know that the astrocytes become activated with this GFAP mutation," Hagemann says. "That activation -- a kind of inflammation -- could be making the environment hostile to young neurons. Or the mutation could be changing the neural stem cells themselves in some other way.

"Medicine advances by teasing things apart," says Hagemann. "A single mutation can work in different ways -- through different chains of cause and effect leading to different symptoms of a disease. In this case it's like the old question of nature versus nurture. Was the stem cell born bad -- was it genetically doomed? Or were the reactive astrocytes in the neighborhood a toxic influence? Or both? This is an important question for Alexander disease and other brain deteriorating disorders, especially with the current focus on stem cells as a source for new neurons and therapy."

Already, the Waisman group is screening drugs that might slow GFAP production. Eventually, Hagemann says, the work may illuminate the role of astrocyte dysfunction in other neural diseases featuring aggregates of misformed proteins, including ALS, Parkinson's, and Alzheimer's disease.


Story Source:

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


Journal Reference:

  1. T. L. Hagemann, R. Paylor, A. Messing. Deficits in Adult Neurogenesis, Contextual Fear Conditioning, and Spatial Learning in a Gfap Mutant Mouse Model of Alexander Disease. Journal of Neuroscience, 2013; 33 (47): 18698 DOI: 10.1523/JNEUROSCI.3693-13.2013

Cite This Page:

University of Wisconsin-Madison. "Rare disease yields clues about broader brain pathology." ScienceDaily. ScienceDaily, 20 November 2013. <www.sciencedaily.com/releases/2013/11/131120100316.htm>.
University of Wisconsin-Madison. (2013, November 20). Rare disease yields clues about broader brain pathology. ScienceDaily. Retrieved July 31, 2014 from www.sciencedaily.com/releases/2013/11/131120100316.htm
University of Wisconsin-Madison. "Rare disease yields clues about broader brain pathology." ScienceDaily. www.sciencedaily.com/releases/2013/11/131120100316.htm (accessed July 31, 2014).

Share This




More Health & Medicine News

Thursday, July 31, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Health Insurers' Profits Slide

Health Insurers' Profits Slide

Reuters - Business Video Online (July 30, 2014) Obamacare-related costs were said to be behind the profit plunge at Wellpoint and Humana, but Wellpoint sees the new exchanges boosting its earnings for the full year. Fred Katayama reports. Video provided by Reuters
Powered by NewsLook.com
Concern Grows Over Worsening Ebola Crisis

Concern Grows Over Worsening Ebola Crisis

AFP (July 30, 2014) Pan-African airline ASKY has suspended all flights to and from the capitals of Liberia and Sierra Leone amid the worsening Ebola health crisis, which has so far caused 672 deaths in Guinea, Liberia and Sierra Leone. Duration: 00:43 Video provided by AFP
Powered by NewsLook.com
At Least 20 Chikungunya Cases in New Jersey

At Least 20 Chikungunya Cases in New Jersey

AP (July 30, 2014) At least 20 New Jersey residents have tested positive for chikungunya, a mosquito-borne virus that has spread through the Caribbean. (July 30) Video provided by AP
Powered by NewsLook.com
Xtreme Eating: Your Daily Caloric Intake All On One Plate

Xtreme Eating: Your Daily Caloric Intake All On One Plate

Newsy (July 30, 2014) The Center for Science in the Public Interest released its 2014 list of single meals with whopping calorie counts. 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