Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Study reveals enzyme function, could help find muscular dystrophy therapies

10.01.2012
Study reveals function of glycosylating enzyme involved in muscular dystrophy, brain development and infection by arenaviruses such as Lassa fever; ability to assay enzyme activity could help screen potential muscular dystrophy therapies

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.

In addition to Campbell, the study team included Kei-ichiro Inamori, Ph.D., and Takako Yoshida-Moriguchi, Ph.D., who were co-first authors of the study, and Yuji Hara, Ph.D., Mary Anderson, and Liping Yu, Ph.D.

The study was funded in part by a National Institutes of Health grant for the Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center at the UI.

Jennifer Brown | EurekAlert!
Further information:
http://www.uiowa.edu

More articles from Life Sciences:

nachricht One step closer to reality
20.04.2018 | Max-Planck-Institut für Entwicklungsbiologie

nachricht The dark side of cichlid fish: from cannibal to caregiver
20.04.2018 | Veterinärmedizinische Universität Wien

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Spider silk key to new bone-fixing composite

University of Connecticut researchers have created a biodegradable composite made of silk fibers that can be used to repair broken load-bearing bones without the complications sometimes presented by other materials.

Repairing major load-bearing bones such as those in the leg can be a long and uncomfortable process.

Im Focus: Writing and deleting magnets with lasers

Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.

Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...

Im Focus: Gamma-ray flashes from plasma filaments

Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.

The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...

Im Focus: Basel researchers succeed in cultivating cartilage from stem cells

Stable joint cartilage can be produced from adult stem cells originating from bone marrow. This is made possible by inducing specific molecular processes occurring during embryonic cartilage formation, as researchers from the University and University Hospital of Basel report in the scientific journal PNAS.

Certain mesenchymal stem/stromal cells from the bone marrow of adults are considered extremely promising for skeletal tissue regeneration. These adult stem...

Im Focus: Like a wedge in a hinge

Researchers lay groundwork to tailor drugs for new targets in cancer therapy

In the fight against cancer, scientists are developing new drugs to hit tumor cells at so far unused weak points. Such a “sore spot” is the protein complex...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

Unique scope of UV LED technologies and applications presented in Berlin: ICULTA-2018

12.04.2018 | Event News

IWOLIA: A conference bringing together German Industrie 4.0 and French Industrie du Futur

09.04.2018 | Event News

 
Latest News

Magnetic nano-imaging on a table top

20.04.2018 | Physics and Astronomy

Start of work for the world's largest electric truck

20.04.2018 | Interdisciplinary Research

Atoms may hum a tune from grand cosmic symphony

20.04.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>