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New Research: Conformation and Accumulation of Proteins Involved in ALS

Amyotrophic lateral sclerosis—better known as ALS or Lou Gehrig’s disease—is one of several progressive neurodegenerative diseases that drastically affect human nerve cells located in the brain and spinal cord. ALS affects the motor neurons spanning from the brain to the spinal cord as well as the body’s muscular tissues. As neurons degenerate and die, the brain can no longer initiate muscle movement—and the associated muscles are profoundly affected. Eventually, many people with ALS can lose their ability to move naturally, eat, speak, and even breathe.

Unfortunately, ALS affects as many as three individuals per 100,000 in the United States, resulting in up to 5,000 new cases per year. Many of these cases occur sporadically or with no known genetic component. However, others appear to form due to the gene encoding errors for a protein called superoxide dismutase 1, or Sod1. New studies regarding this mutant protein’s behavior could reveal a great deal about the mechanisms behind ALS.

The Role of Sod1

In the normal human body, Sod1 proteins and other similar proteins protect the body against oxidation damage. Oxidative stress can create free radicals that damage cell components and make them less effective. When Sod1 is present and performs its normal function, it reduces the opportunity for cell oxidative damage.

However, when mutations alter Sod1, it can no longer fold correctly and cannot perform its regular function. Oxidative stress increases, and the misfolded, altered Sod1 accumulates within motor nerve cells. The presence of this protein aggregation damages neurons, causing nerve cell death and perhaps even contributing to sporadic (non-genetically linked) cases of ALS.

New Research

Scientists at the Federal University of Rio de Janeiro and the University of Gottingen, Germany, have teamed up to study why Sod1 misbehaves and forms these harmful aggregates. Using laboratory models made of simpler organisms like yeasts, researchers mimicked conditions within normal human cells in addition to creating models to simulate the circumstances of genetically linked ALS. 

Using advanced molecular imaging techniques, researchers were able to see the very Sod1 protein complexes believed to contribute to ALS in action within a live cell. The protein complexes formed by normal Sod1 genes and those formed by mutated Sod1 genes showed marked differences. Through this study, researchers were able to identify instances in which the mutated protein copy altered the normal protein copy’s behavior, forming altered Sod1 complexes that were much less effective and much more prone to aggregating.

Future Implications

With this new information about protein aggregations, researchers hope to develop therapies that can target the Sod1 protein. Potential removal of the protein’s mutant form could enable the body to produce normal Sod1 and stem the development of the very aggregations that seem to trigger ALS. Early identification of individuals harboring altered copies of the Sod1 gene may enable them to receive therapies before ALS symptoms even begin.

In the future, therapies targeting the mechanisms behind ALS are looking brighter than ever before.