Featured Research

from universities, journals, and other organizations

Rare, lethal childhood disease tracked to failure to degrade nerve cells' filaments

Date:
December 17, 2012
Source:
American Society for Cell Biology
Summary:
A defective protein explains why a failure in protein degradation would lead to the massive aggregations of a class of filaments that disrupt the functioning of neurons of children with the rare, untreatable genetic disease giant axonal neuropathy. Discovery may have implications for more common types of neurodegenerative diseases such as Alzheimer's.

For the first time, a defective protein that plays a specific role in degrading intermediate filaments (IF), one of three classes of filaments that form the structure of nerve cells, has been discovered by an international team of researchers.

The defective protein, gigaxonin, which was first identified in children with a rare and untreatable genetic disease called giant axonal neuropathy (GAN), according to Saleemulla Mahammad, PhD, of the Northwestern Feinberg School of Medicine in Chicago, who presented the data on Dec. 17 at the American Society for Cell Biology Annual Meeting in San Francisco.

The identification of gigaxonin's specific role explains why a failure in protein degradation would lead to massive aggregations of IF in the neuronal cells of GAN children, said Dr. Mahammad who is in the laboratory of Robert D. Goldman, PhD, and collaborated with Puneet Opal, MD, PhD, at Northwestern along with researchers at INSERM in Montpelier, France and the Universitι Laval in Quebec, Canada.

The GAN gene was first identified in 2000 by Dr. Pascale Bomont, now at the French INSERM neurological institute in Montpellier, who reported that it encoded for the protein gigaxonin. Based on sequence homology, gigaxonin is involved in the normal turnover of proteins by the well-studied ubiquitin-proteasome system. But it wasn't clear why a failure in protein degradation would lead to massive aggregations of IF in a patient's neuronal cells.

Because it is not possible to study nerve cells experimentally from patients, Dr. Mahammad and collaborators instead used fibroblasts from skin biopsies of children with GAN because previous studies had revealed that other classes of IF are also altered in GAN patients. In particular, the IF vimentin expressed in fibroblasts of children with GAN also forms abnormally large aggregates. These cells can readily be obtained from skin biopsies and grown in lab cultures.

When the researchers introduced the gigaxonin gene into both control and patient fibroblasts, the results were dramatic. In the fibroblasts cultured from GAN patients, the complex network of vimentin filaments and abnormal aggregates disappeared. The vimentin filaments in the control cells also disappeared following the overexpression of the gigaxonin protein. Boosting gigaxonin to higher levels in normal cultured nerve cells also led to a degradation of neuronal forms of IF. However, the cytoskeleton's two other major systems, microtubules and actin filaments, were not affected by this treatment.

These findings point to a central role for gigaxonin in regulating the normal turnover of IF proteins. When gigaxonin is defective, neurofilaments pile up, and eventually the aggregates disrupt the normal functioning of nerve cells in GAN.

Gigaxonin is the first factor to be identified that plays a specific role in the degradation of several types of IF proteins, including neurofilaments, according to Dr. Mahammad. This discovery may have implications for more common types of neurodegenerative diseases that are also characterized by large accumulations of IF proteins, including Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, Charcot-Marie-Tooth (CMT) disease, neuronal intermediate filament inclusion disease (NIFID), and diabetic neuropathy.

GAN is an extremely rare genetic disorder that strikes at both the peripheral and central nervous systems of children. The leading GAN disease foundation, Hannah's Hope Fund, currently knows of 31 cases worldwide, 19 in the United States alone. But its rarity doesn't dull its severity in children affected by GAN. There are no symptoms at birth, but by age three the first signs of muscle weakness usually appear and progress slowly but steadily. With increasing difficulty in walking and coordinating hand movements, children with GAN are often wheelchair-bound by age 10. Over time, they become dependent on feeding and breathing tubes. A few will survive into young adulthood. The pathological markers for GAN are swollen (thus "giant") axons, filled with abnormal aggregates of neurofilaments, rich in Ifs.

This research was supported by NIH grant 1P01GM096971-01 and Hannah's Hope Fund.


Story Source:

The above story is based on materials provided by American Society for Cell Biology. Note: Materials may be edited for content and length.


Cite This Page:

American Society for Cell Biology. "Rare, lethal childhood disease tracked to failure to degrade nerve cells' filaments." ScienceDaily. ScienceDaily, 17 December 2012. <www.sciencedaily.com/releases/2012/12/121217140533.htm>.
American Society for Cell Biology. (2012, December 17). Rare, lethal childhood disease tracked to failure to degrade nerve cells' filaments. ScienceDaily. Retrieved October 21, 2014 from www.sciencedaily.com/releases/2012/12/121217140533.htm
American Society for Cell Biology. "Rare, lethal childhood disease tracked to failure to degrade nerve cells' filaments." ScienceDaily. www.sciencedaily.com/releases/2012/12/121217140533.htm (accessed October 21, 2014).

Share This



More Health & Medicine News

Tuesday, October 21, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

How Nigeria Beat Its Ebola Outbreak

How Nigeria Beat Its Ebola Outbreak

Newsy (Oct. 20, 2014) — The World Health Organization has declared Nigeria free of Ebola. Health experts credit a bit of luck and the government's initial response. Video provided by Newsy
Powered by NewsLook.com
Another Study Suggests Viagra Is Good For The Heart

Another Study Suggests Viagra Is Good For The Heart

Newsy (Oct. 20, 2014) — An ingredient in erectile-dysfunction medications such as Viagra could improve heart function. Perhaps not surprising, given Viagra's history. Video provided by Newsy
Powered by NewsLook.com
Ebola Worries End for Dozens on U.S. Watch Lists

Ebola Worries End for Dozens on U.S. Watch Lists

Reuters - US Online Video (Oct. 20, 2014) — Forty-three people who had contact with Thomas Eric Duncan, the first person diagnosed with Ebola in the U.S., were cleared overnight of twice-daily monitoring after 21 days of showing no symptoms. Rough Cut (no reporter narration). Video provided by Reuters
Powered by NewsLook.com
CDC Calls for New Ebola Safety Guidelines

CDC Calls for New Ebola Safety Guidelines

AP (Oct. 20, 2014) — Centers for Disease Control and Prevention Director Dr. Tom Frieden laid out new guidelines for health care workers when dealing with the deadly Ebola virus including new precautions when taking off personal protective equipment. (Oct. 20) Video provided by AP
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