Researchers from Brandeis University (BrandUni) have made a significant advance in the effort to understand amyotrophic lateral sclerosis (ALS) by successfully reversing the toxicity of a 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.

The Petsko/Ringe laboratory reached 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 the risk for the more common forms of ALS, it’s one of those genes, FUS/TLS, which got the attention of the Petsko/Ringe team. According to Gregory A. Petsko, professor of chemistry and biochemistry, post-mortem examinations of certain ALS victims show that the dying neurons contain clumps of the FUS/TLS protein.  Normally this protein lives in the nucleus of the cell, which is where the chromosomes are.  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.

Scientists 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. 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 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. The second thing is that it killed the yeast cell, so scientists 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. 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. By a series of genetic experiments, 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. Gregory A. Petsko believes that if they can do that with the expression with another human gene they could probably do that with a drug.