Mutation of SOD1 gene is another step toward unraveling the genetic, cellular mysteries of ALS

Mutations in a gene called SOD1 lead to the development of cellular anomalies associated with amyotrophic lateral sclerosis (ALS), according to a new study using animal models of the disease. Such anomalies included deficient regulation of amino acid levels, which are crucial for protein production and cell activity, but could be reverted supplements of the amino acid L-Leucine.

The study, “New Links Between SOD1 And Metabolic Dysfunction From A Yeast Model Of Amyotrophic Lateral Sclerosis,” was published in the Journal of Cell Science. This discovery is another step toward deciphering the genetic and cellular mysteries about how ALS develops.

Many genes have been associated with the loss of muscular function, the hallmark of ALS. Up to 20% of hereditary cases of ALS are related with mutations in the SOD1 gene, which encodes a protein that participates in the process of energy production to sustain the body’s functions. Although more than 150 mutations have been implicated in ALS, exactly how these mutations relate to the cellular dysfunction leading to disease progression remains elusive.

To address this matter, researchers introduced several ALS-linked mutations into the SOD1 gene of the yeast Saccharomyces cerevisiae.

Mutations in the SOD1 gene led to the production of an unstable form of the corresponding protein, with toxic effects to cells. Contrary to what had been suggested by previous studies, these mutations did not lead to the formation of Sod1 protein aggregates or interfere with energy production in the mitochondria (the cell’s powerhouse). But the mutations did induce metabolic stress, disrupting several reactions important to recycle malfunctioning or old molecules, and stopped cell growth by causing a striking inability of the cell to control amino acid levels.

Researchers also analyzed the effect induced by increased levels of Sod1, which in previous studies with mice has shown to result in ALS. Similarly, promoting the expression of the SOD1 gene in the worm Caenorhabditis elegans also led to motor neuron dysfunction. Importantly, supplementing the media upon which these worms were growing and feeding with the amino acid L-leucine rescued motor neuron degeneration.

Together, these results show that mutations affecting the stability or increasing the production of the Sod1 protein lead to the activation of molecular pathways that trigger motor neuron dysfunction and the development of ALS.

“It is likely that mutations that destabilise the Sod1 protein lead to structurally altered soluble forms that have deleterious effects on the cell,” the authors concluded. “Within this hypothesis it is also possible that native Sod1 molecules that are not properly [produced] also exhibit toxic effects. This proposal is supported by the fact that over-expression of native Sod1 can lead to disease in [animal] models,” they said.