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 Tracing the evolution of vision
23.08.2019 | University of Göttingen

nachricht Caffeine does not influence stingless bees
23.08.2019 | Johannes Gutenberg-Universität Mainz

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Hamburg and Kiel researchers observe spontaneous occurrence of skyrmions in atomically thin cobalt films

Since their experimental discovery, magnetic skyrmions - tiny magnetic knots - have moved into the focus of research. Scientists from Hamburg and Kiel have now been able to show that individual magnetic skyrmions with a diameter of only a few nanometres can be stabilised in magnetic metal films even without an external magnetic field. They report on their discovery in the journal Nature Communications.

The existence of magnetic skyrmions as particle-like objects was predicted 30 years ago by theoretical physicists, but could only be proven experimentally in...

Im Focus: Physicists create world's smallest engine

Theoretical physicists at Trinity College Dublin are among an international collaboration that has built the world's smallest engine - which, as a single calcium ion, is approximately ten billion times smaller than a car engine.

Work performed by Professor John Goold's QuSys group in Trinity's School of Physics describes the science behind this tiny motor.

Im Focus: Quantum computers to become portable

Together with the University of Innsbruck, the ETH Zurich and Interactive Fully Electrical Vehicles SRL, Infineon Austria is researching specific questions on the commercial use of quantum computers. With new innovations in design and manufacturing, the partners from universities and industry want to develop affordable components for quantum computers.

Ion traps have proven to be a very successful technology for the control and manipulation of quantum particles. Today, they form the heart of the first...

Im Focus: Towards an 'orrery' for quantum gauge theory

Experimental progress towards engineering quantized gauge fields coupled to ultracold matter promises a versatile platform to tackle problems ranging from condensed-matter to high-energy physics

The interaction between fields and matter is a recurring theme throughout physics. Classical cases such as the trajectories of one celestial body moving in the...

Im Focus: A miniature stretchable pump for the next generation of soft robots

Soft robots have a distinct advantage over their rigid forebears: they can adapt to complex environments, handle fragile objects and interact safely with humans. Made from silicone, rubber or other stretchable polymers, they are ideal for use in rehabilitation exoskeletons and robotic clothing. Soft bio-inspired robots could one day be deployed to explore remote or dangerous environments.

Most soft robots are actuated by rigid, noisy pumps that push fluids into the machines' moving parts. Because they are connected to these bulky pumps by tubes,...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

The power of thought – the key to success: CYBATHLON BCI Series 2019

16.08.2019 | Event News

4th Hybrid Materials and Structures 2020 28 - 29 April 2020, Karlsruhe, Germany

14.08.2019 | Event News

What will the digital city of the future look like? City Science Summit on 1st and 2nd October 2019 in Hamburg

12.08.2019 | Event News

 
Latest News

Making small intestine endoscopy faster with a pill-sized high-tech camera

23.08.2019 | Medical Engineering

More reliable operation offshore wind farms

23.08.2019 | Power and Electrical Engineering

Tracing the evolution of vision

23.08.2019 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>