Researchers make strides in understanding amyotrophic lateral sclerosis
These yeast cells are expressing human FUS/TLS (green spots) in cytosol, with blue stain of nucleus. Credit: Brandeis University
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.
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."
Provided by Brandeis University
- Studies of mutated protein in Lou Gehrig's disease reveal new paths for drug discovery Apr 26, 2011 | not rated yet | 0
- Researchers find potential in yeast for selecting Lou Gehrig's disease drugs Apr 17, 2008 | not rated yet | 0
- Study identifies new gene associated with ALS Feb 26, 2009 | not rated yet | 0
- New discovery may block ALS disease process Apr 19, 2011 | not rated yet | 0
- Researchers discover genetic link between both types of ALS May 05, 2010 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Why is zone 1 in liver more prone to ischemic injury?
May 23, 2013 Hi, Is it because around central vein, there is only deoxygenated blood from the vein where as in the periphery there is hepatic artery. Also why...
How can there be villous adenoma in colon, if there are no villi there
May 22, 2013 As title suggest. Thanks :smile:
How can there be a term called "intestinal metaplasia" of stomach
May 21, 2013 Hello everyone, Ok Stomach's normal epithelium is simple columnar, now in intestinal type of adenocarcinoma of stomach it undergoes "intestinal...
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
- More from Physics Forums - Medical Sciences
More news stories
By discovering the new mechanism by which estrogen suppresses lipid synthesis in the liver, UC Irvine endocrinologists have revealed a potential new approach toward treating certain liver diseases.
Medical research May 23, 2013 | 5 / 5 (1) | 0 |
Aortic arch pulse wave velocity, a measure of arterial stiffness, is a strong independent predictor of disease of the vessels that supply blood to the brain, according to a new study published in the June issue the journal ...
Medical research May 23, 2013 | not rated yet | 0
Since the discovery of Prontosil in 1932, sulfonamide antibiotics have been used to combat a wide spectrum of bacterial infections, from acne to chlamydia and pneumonia. However, their side effects can include serious neurological ...
Medical research May 23, 2013 | 3 / 5 (1) | 0 |
Scientists at the National Institutes of Health report they have discovered in mouse studies that a small molecule released in the spinal cord triggers a process that is later experienced in the brain as ...
Medical research May 23, 2013 | 5 / 5 (3) | 0 |
Spanish researchers have discovered that the daily clearance of neutrophils from the body stimulates the release of hematopoietic stem cells from the bone marrow into the bloodstream, according to a report published today ...
Medical research May 23, 2013 | 5 / 5 (2) | 0
(HealthDay)—Animals make great companions for senior citizens, but elderly people who always drive with a pet in the car are far more likely to crash than those who never drive with a pet, researchers have ...
7 minutes ago | not rated yet | 0
Coenzyme Q10 decreases all cause mortality by half, according to the results of a multicentre randomised double blind trial presented today at Heart Failure 2013 congress. It is the first drug to improve heart failure mortality ...
8 hours ago | 5 / 5 (2) | 5
Heart failure accelerates the aging process and brings on early andropausal syndrome (AS), according to research presented today at the Heart Failure Congress 2013. AS, also referred to as male 'menopause', was four times ...
8 hours ago | not rated yet | 1
Mortality and length of stay are highest in heart failure patients admitted in January, on Friday, and overnight, according to research presented today at the Heart Failure Congress 2013. The analysis of nearly 1 million ...
8 hours ago | not rated yet | 0
(AP)—Department of Justice lawyers have again asked a federal appeals court in New York to delay lifting age restrictions and prescription requirements on an emergency contraceptive popularly known as the morning-after ...
8 hours ago | not rated yet | 0
Talking on a hands-free device while behind the wheel can lead to a sharp increase in errors that could imperil other drivers on the road, according to new research from the University of Alberta.
23 hours ago | not rated yet | 1