Amyotrophic lateral sclerosis (ALS), ravages nerve cells in the spinal cord and brain. It is at times called Lou Gehrig’s disease, named after the famous baseball player who died of ALS.
A recent article in MedicalXpress reports that approximately 30,000 people in the United States are currently living with ALS and experiencing progressive loss of motor function. It is believed that the majority of ALS patients die within 5 years of diagnosis.
A research team at Northeastern University led by Associate Jeffrey Agar has identified a small molecule called a ‘linker’ that targets and stabilizes an enzyme that prevents the destruction of cells. Prof. Agar devoted the past twelve years studying the mechanisms of ALS and researching various ways that it can be prevented. Prof. Agar, associate professor of chemistry and pharmaceutical sciences at Northeastern, has spent the last 12 years studying the mechanism of ALS and researching ways to prevent its progression.
Post-Translational Modifications (PTM)
Using animal models for its pre-clinical ALS study, the Northeastern team characterized PTM as chemical changes occurring after a protein has been produced. Using a variety of tests, the team analyzes changes in peptide, protein, and lipid expression to determine which changes may have toxic or structural consequences. The new research has been published by the PLOS Biology journal stating that the Northeastern University team has found a method of homing in on an enzyme that protects cells from toxic byproducts that are transmitted by breathing oxygen and consuming food.
About the SOD1 Enzyme
Inherited mutations to SOD1 are the primary cause of ALS yet other mutations may occasionally occur with no family history. The SOD1 gene generates instructions for the creation of an enzyme called superoxide dismutase located in cells in every part of the body. When the SOD1 gene is mutated and loses its shape, it can no longer perform its normal tasks. More importantly, when a SOD1 gene misfunctions it triggers a buildup of protein clumps that are the hallmark of various disorders such as Alzheimer’s and Parkinson’s.
About the Discovery
Prof. Agar explained that during the decade, he and his team discovered and have been testing a ‘molecular stabilizer’ called S-XL6 which can be compared to a ‘stitch’. S-XL6 controls the protein by forcing it to stay in the proper configuration.
Once discovered, the team still faced the challenge of locating a stitch that focused on proteins thereby targeting only SOD1 as an off-target attack can destroy the remaining target and poison the host.
The molecule was tested in genetically modified mice that developed a form of ALS. In addition to restoring the protein’s function, the secondary effects, SX-L6 also prevented secondary toxic effects.
The team reported that it was able to stabilize 60 to 70% of the SOD1 proteins in brain cells and 90% of the proteins in the blood cells.
The next step is to obtain permission to investigate the molecule in a clinical trial. Prof. Agar suggests that their discovery might be combined with an FDA approved regimen that works by the reduction of SOD1 genes produced by the body.
About ALS
ALS is a nervous system disease affecting the nerve cells in the brain and spinal cord. Muscles become weak causing paralysis. The disease causes trouble swallowing, speaking, breathing and slurred speech. Currently there is no cure.
