Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Study at TSRI links dozens of proteins to several rare muscle and nerve degeneration diseases

05.09.2003


A team of scientists at The Scripps Research Institute (TSRI) has identified more than 50 previously unknown proteins and associates several of them with rare human muscle and nerve degeneration diseases. The team is publishing their findings this week in the journal Science.



Led by TSRI Professors Larry Gerace and John R. Yates III, the team used a technique called subtractive proteomics to identify 62 new proteins in the inner nuclear membrane of the human cell. The team demonstrated that 23 of these proteins are linked with strong probability to 14 rare muscle-wasting diseases such as congenital muscular dystrophy, Limb-Girdle muscular dystrophy, and spinal muscular atrophy, and several forms of the neurodegenerative Charcot-Marie-Tooth disease.

Knowing the proteins that may cause or contribute to these diseases is a first step in the long process of looking for ways to detect, prevent, or treat them.


This study has the potential to clarify a significant number of the more than 300 human dystrophies for which a causative gene has not been identified.

"To understand how these diseases happen, we need to understand more about the players--the network of interlinked proteins," says Gerace.

Muscular Dystrophies and the Nuclear Membrane

Many rare but devastating diseases have been linked to the inner nuclear membrane, which lines the nuclear envelope compartmentalizing the cell’s genetic material or DNA. On the inner surface of the membrane is a structure referred to as the lamina. The lamina is important for maintaining the shape and size of the nucleus. It also contributes to the specialized functions of different human cells, for example, enabling muscle cells to perform their particular functions and brain cells to perform theirs.

The lamina is largely composed of proteins called lamins, which are like bricks that form a scaffold-like structure for the nucleus. The lamina also contains membrane proteins that dock at the lamins.

"There have been a number of human muscular and neuronal dystrophies that have been linked to [these] proteins," says Gerace. "When certain lamins and inner membrane proteins are mutated, they cause disease."

Because of this link between lamina proteins and disease, scientists would like to know the identity of all the proteins in the lamina, and previous studies have identified about 20 lamina proteins.

In their current study, Gerace and Yates used a technique called subtractive proteomics to identify 62 more candidate human nuclear membrane proteins.

In the study, TSRI Postdoctoral Fellow Eric Schirmer demonstrates that the genes encoding 23 of these candidate human nuclear membrane proteins are in regions of the genome that have already been implicated in 14 muscle- and neuro-degenerative diseases.

However, many of these regions have hundreds of genes in them; so the identification of these disease gene candidates should greatly focus identification of the culprits.

"It’s highly likely that some of these diseases will be due to [the newly identified] nuclear envelope proteins," says Gerace. "This is a pretty big step forward."

The Power of Subtractive Proteomics

Where "genomics" maps the DNA sequence and seeks to identify all the genes in an organism, "proteomics" takes a step further by asking where and when those genes are actually expressed as proteins.

One of the most important techniques emerging for proteomics studies is humbly referred to as MudPIT--Multidimensional Protein Identification Technology-which Yates has pioneered in the last few years. Using this technique, scientists like Yates are able to analyze and identify an enormous number of proteins in a complex mixture.

MudPIT basically combines liquid chromatography (which is like a molecular "sieve" that separates a complex mixture into its component parts) with tandem mass spectrometry (which identifies the components based on their masses). The instrument detects these masses and uses sophisticated software to identify thousands of separate proteins.

But MudPIT alone was not enough in this case, because the inner nuclear membrane is in contact with other structures of the cell and cannot be isolated without contaminating material. Identifying which proteins are from the inner nuclear membrane and which are contaminants presented a huge problem.

So the team used a simple subtractive technique to deal with this. They analyzed the nuclear membrane components with contaminants, containing 2,071 different proteins, and subtracted out the separately isolated contaminants, which accounted for more than 40 percent of the membrane proteins. From this list they were able to apply computational methods to limit the final list of new human nuclear membrane proteins to 62.

The scientists then took eight of these proteins at random and demonstrated that they all indeed targeted to the nuclear membrane.

The new nuclear membrane proteins identified in this study map to chromosomal regions where the following dystrophies have been localized:

Congenital Ptosis, hereditary type 1
Charcot-Marie-Tooth Disease 2A
Congenital Muscular Dystrophy 1B
Limb-Girdle Muscular Dystrophy 2B
Charcot-Marie-Tooth Disease 2A
Facioscapulohumeral Muscular Dystrophy (FSH)
Spinal Muscular Atrophy, Types 1, 2, and 3
Limb-Girdle Muscular Dystrophy 1A/1B
Arthogryposis: neurogenic, mild
Blepharophimosis 2
Charcot-Marie-Tooth Disease 2A
Distal Arthrogryposis, type 2B
Congenital Fibrosis of Extraocular Muscles 1
Distal Myopathy

The article, "Nuclear Membrane Proteins With Potential Disease Links Found By Subtractive Proteomics" was authored by Eric C. Schirmer, Laurence Florens, Tinglu Guan, John R. Yates III, and Larry Gerace and will appear in the September 5, 2003 issue of the journal Science. See: http://www.sciencemag.org.


This work was supported by the National Institutes of Health.


Keith McKeown | EurekAlert!
Further information:
http://www.scripps.edu/
http://www.sciencemag.org

More articles from Health and Medicine:

nachricht A promising target for kidney fibrosis
21.04.2017 | Brigham and Women's Hospital

nachricht Stem cell transplants: activating signal paths may protect from graft-versus-host disease
20.04.2017 | Technische Universität München

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

7th International Conference on Crystalline Silicon Photovoltaics in Freiburg on April 3-5, 2017

03.04.2017 | Event News

 
Latest News

Fraunhofer HHI with latest VR technologies at NAB in Las Vegas

24.04.2017 | Trade Fair News

New quantum liquid crystals may play role in future of computers

21.04.2017 | Physics and Astronomy

A promising target for kidney fibrosis

21.04.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>