Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers at Brandeis University make strides in understanding amyotrophic lateral sclerosis

27.04.2011
Laboratory reports success in blocking the lethal effects of ALS

Brandeis researchers have made a significant advance in the effort to understand amyotrophic lateral sclerosis (ALS) by successfully reversing the toxicity of the mutated protein in the familial type of the disease.


These yeast cells are expressing human FUS/TLS (green spots) in cytosol, with blue stain of nucleus. Credit: Brandeis University

Currently there is no cure or prevention for the disease, which affects nerve cells in the brain and the spinal cord. Most frequently referred to as Lou Gehrig's disease, after its most famous victim, ALS typically causes death due to respiratory paralysis within three to five years of onset. The only approved drug, Riluzole, can extend the lifespan of some patients by three months.

In a paper published Tuesday, April 26 in PLoS Biology, the Pestko/Ringe laboratory reports success in blocking the lethal effects of the gene by placing several human genes into a yeast cell that shows many similar features to the disease-causing proteins.

Genes have been identified for many of the 10 percent of ALS cases that run in families. People with one of those mutant genes are likely to develop the disease. While a few of those genes might also contain mutations that increase risk for the more common forms of ALS, it's one of those genes, FUS/TLS, which got the attention of the Pesko/Ringe team.

"We started to work on this project when we learned that mutations of FUS/TLS gene were linked to familial ALS by our collaborators, Dr. Robert Brown's group, at the University of Massachusetts medical school," says Shulin Ju, a post-doctoral researcher and first author of the paper. The collaboration also includes members of Whitehead Institute for Biomedical Research, MIT, Harvard University, University of Rochester and the University of Pennsylvania.

Here is some of the biology and chemistry behind the research:

Post-mortem examinations of certain ALS victims show that the dying neurons contain clumps of the FUS/TLS protein. What's interesting, says Gregory A. Petsko, professor of chemistry and biochemistry, is where these inclusions are.

"Normally this protein lives in the nucleus of the cell, which is where the chromosomes are," says Petsko. "In this disease, it seems to move from the nucleus out into the cytoplasm of the cell, the main part, and that's where it forms the inclusions that are associated with the disease."

Petsko and Ringe's team wanted to study this process in an organism on which they could perform sophisticated genetic screenings and detailed biochemical experiments, which can not be done in human cells. So they chose yeast.

"It may seem kind of crazy to think of doing yeast experiments on a human neurologic disease, since yeast has no brain or spinal cord or any neurons at all," says Petsko, "But a yeast cell isn't that different from a typical human cell."

The team inserted the FUS/TLS gene into a yeast cell with the hope that it would create the same observable characteristics as the mutant protein does in a human cell. When they did, Petsko says, two remarkable things happened.

"First thing is that the human protein wasn't in the nucleus, it moved to the cytoplasm of the cell just like it did in the human disease— and it formed inclusions," says Petsko. "The second thing is that it killed the yeast cell, so we got in yeast a pretty faithful replication of some of the features of the human disease caused by mutation of this gene."

The next step was to find out what part of the protein was necessary in order to keep it in the nucleus and what part was necessary to send it to the cytoplasm.

Petsko then asked, "If we started deleting sections of the protein could we force the protein to always be in the cytoplasm or always be in the nucleus?"

When they performed the experiment with yeast they found that the area of the gene where the disease-causing mutations occur was the area responsible for keeping it in the nucleus; when that area is mutated, the gene leaves the nucleus for the cytoplasm.

"We want to keep it in the nucleus but you can't do that with the mutants easily because the part responsible for keeping it in the nucleus has been destroyed by the mutation, which is why you have the disease," says Petsko.

They then asked whether they could prevent the yeast cells from being killed by this protein by placing some other protein inside.

In other words, Petsko says, could they find a protein that would rescue the cell from the toxicity of FUS/TLS?

By a series of genetic experiments described in the paper, they were able to identify several human genes which, when inserted along with FUS/TLS gene, rendered FUS/TLS protein no longer toxic to yeast. The cells survived.

"And then we got the surprise of our life," says Petsko. "When we looked at those cells, FUS/TLS protein was still in the cytoplasm, and still forming inclusions. In other words, we were able to eliminate the toxicity of the protein without sending it back to the nucleus."

What this told them was that aggregating and being in the cytoplasm didn't necessarily have to be toxic as long as the rescue protein that they found was introduced.

That, says Petsko, got them really excited, because "if you can do that with the expression with another human gene you could probably do that with a drug."

Susan Chaityn Lebovits | EurekAlert!
Further information:
http://www.brandeis.edu

Further reports about: Brandeis Researchers human cell nerve cell spinal cord

More articles from Life Sciences:

nachricht Cryo-electron microscopy achieves unprecedented resolution using new computational methods
24.03.2017 | DOE/Lawrence Berkeley National Laboratory

nachricht How cheetahs stay fit and healthy
24.03.2017 | Forschungsverbund Berlin e.V.

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Argon is not the 'dope' for metallic hydrogen

24.03.2017 | Materials Sciences

Astronomers find unexpected, dust-obscured star formation in distant galaxy

24.03.2017 | Physics and Astronomy

Gravitational wave kicks monster black hole out of galactic core

24.03.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>