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 Satellites, airport visibility readings shed light on troops' exposure to air pollution
09.12.2016 | Veterans Affairs Research Communications

nachricht Oxygen can wake up dormant bacteria for antibiotic attacks
08.12.2016 | Penn State

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: Electron highway inside crystal

Physicists of the University of Würzburg have made an astonishing discovery in a specific type of topological insulators. The effect is due to the structure of the materials used. The researchers have now published their work in the journal Science.

Topological insulators are currently the hot topic in physics according to the newspaper Neue Zürcher Zeitung. Only a few weeks ago, their importance was...

Im Focus: Significantly more productivity in USP lasers

In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.

Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

Researchers identify potentially druggable mutant p53 proteins that promote cancer growth

09.12.2016 | Life Sciences

Scientists produce a new roadmap for guiding development & conservation in the Amazon

09.12.2016 | Ecology, The Environment and Conservation

Satellites, airport visibility readings shed light on troops' exposure to air pollution

09.12.2016 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>