Navigation Links
Study reveals enzyme function, could help find muscular dystrophy therapies
Date:1/9/2012

Researchers at the University of Iowa have worked out the exact function of an enzyme that is critical for normal muscle structure and is involved in several muscular dystrophies. The findings, which were published Jan. 6 in the journal Science, could be used to develop rapid, large-scale testing of potential muscular dystrophy therapies.

The enzyme, called LARGE, adds a critical sugar chain onto an important membrane protein called dystroglycan. This sugar chain acts like a glue allowing dystroglycan to attach to other proteins and by doing so, reinforce cell membranes in many tissues including muscle and brain. Dystroglycan does not function properly without this sugar link, and that malfunction causes muscular dystrophies and brain abnormalities.

"LARGE is a critical enzyme involved in maintaining muscle cell viability," says Kevin Campbell, Ph.D., professor and head of molecular physiology and biophysics at the UI Carver College of Medicine and a Howard Hughes Medical Institute investigator. "It adds on a unique sugar chain that allows the muscle cell to protect its membrane from injury. By figuring out the function of this enzyme we've finally identified this critical sugar link."

The new study shows that the enzyme activity of LARGE has two specific sugar-adding functions -- it transfers the sugars xylose and glucuronic acid. Using nuclear magnetic resonance analysis (NMR), the team was also able to determine the precise structure of the sugar chain produced by LARGE, which has not been seen before.

The study confirmed that this unique sugar chain is responsible for dystroglycan's ability to attach to its protein partners, which include laminin in muscle and neurexin in brain.

In addition to LARGE, several other enzymes are involved in building the important dystroglycan sugar chain, and mutations in all these enzymes cause congenital muscular dystrophies collectively known as secondary dystroglycanopathies. These disorders include Fukuyama Congenital Muscular Dystrophy, Walker-Warburg Syndrome, Muscle-Eye-Brain disease, Congenital Muscular Dystrophy 1C and 1D, and limb-girdle muscular dystrophy 2I.

However, in all cases, the part of the sugar chain that is critical for dystroglycan function is the part that is added by LARGE. Furthermore, work from Campbell's lab has shown that boosting LARGE activity in cells from patients with these types of muscular dystrophies is sufficient to restore dystroglycan function and overcome the defects in the cells.

By understanding what the LARGE enzyme does, the researchers have now been able to develop a test, or assay, to monitor enzyme activity.

"It's exciting that we now have this enzyme assay, which could be used in a large-scale high-throughput screen for drugs that increase (or decrease) LARGE activity," Campbell says.

Using the assay to identify compounds that boost LARGE activity might lead to potential treatments for the secondary dystroglycanopathies. The assay could also be used to look at variations in LARGE activity in patients' cells. This may help identify patients who are affected by these LARGE-related muscular dystrophies.

LARGE activity is important in other diseases

The unusual sugar chain that LARGE builds onto dystroglycan is also implicated in other diseases. A group of viruses that includes Lassa fever appear to require the sugar chain to infect cells. Lassa fever is a hemorrhagic illness that can cause serious disease and death.

Now that the researchers have determined the make-up of the unusual sugar, Campbell suggests that it will be possible to make and test it as a therapeutic to block or reduce infection by these viruses.

Campbell is also excited by another aspect of the Lassa fever link. A genome-wide study of populations in West Africa where Lassa fever is endemic suggests that the LARGE gene may be modified in this population. Campbell speculates that altering LARGE activity might provide some protection against infection by the Lassa fever virus. In the future, he hopes to use his team's newly developed enzyme assay to investigate if LARGE activity is altered in this population.


'/>"/>

Contact: Jennifer Brown
jennifer-l-brown@uiowa.edu
319-356-7124
University of Iowa Health Care
Source:Eurekalert

Related biology news :

1. Study finds age-related effects in MS may be reversible
2. Study finds air pollution linked to diabetes and hypertension in African-American women
3. Scripps Research Scientist wins pair of grants to study critical component of memory
4. Study uncovers a molecular maturation clock that modulates branching architecture in tomato plants
5. Study examines how diving marine mammals manage decompression
6. UMDs START gets $3.6 million to study terrorisms human causes and consequences
7. Human skull study causes evolutionary headache
8. Study reveals turn signals for neuron growth
9. Hellbender salamander study seeks answers for global amphibian decline
10. Study reveals gender bias of prospective parents
11. Wayne State study finds soybean compounds enhances effects of cancer radiotherapy
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:4/11/2017)... 11, 2017 Crossmatch®, a globally-recognized leader ... today announced that it has been awarded a ... Activity (IARPA) to develop next-generation Presentation Attack Detection ... "Innovation has been a driving force within Crossmatch ... allow us to innovate and develop new technologies ...
(Date:4/5/2017)... , April 5, 2017  The Allen Institute for ... Cell Explorer: a one-of-a-kind portal and dynamic digital window ... imaging data, the first application of deep learning to ... stem cell lines and a growing suite of powerful ... for these and future publicly available resources created and ...
(Date:3/30/2017)... -- On April 6-7, 2017, Sequencing.com will host the world,s ... at Microsoft,s headquarters in Redmond, Washington ... health and wellness apps that provide a unique, personalized ... is the first hackathon for personal genomics and the ... the genomics, tech and health industries are sending teams ...
Breaking Biology News(10 mins):
(Date:6/22/2017)... PA (PRWEB) , ... June 22, 2017 , ... ... and superior results to clients throughout the biopharma and life sciences industries, continue ... the industry is seeing. Tunnell’s Kip Wolf will be speaking on “The State ...
(Date:6/22/2017)... ... June 22, 2017 , ... RURO, Inc., ... Limfinity® version 6.5, a content-packed update to the Limfinity® framework. , LimitLIS® and ... and more diverse base of customers among labs and other businesses. Limfinity® 6.5 ...
(Date:6/20/2017)... Hill, CT (PRWEB) , ... June 20, 2017 ... ... support, today announced that the CTNext board of directors has formed a Higher ... by a working group composed of institution presidents and other high-ranking representatives from ...
(Date:6/20/2017)... ... 20, 2017 , ... HorizonScan is providing food and ingredient ... likely threat to their products at the annual IFT conference in Las Vegas, ... expo attracts over 20,000 attendees representing food science professionals from over 90 countries ...
Breaking Biology Technology: