They identify a possible origin of amyotrophic lateral sclerosis

The amyotrophic lateral sclerosis (ALS) It is a degenerative disease for which today the causes are unknown and there is no efficient treatment. Now, Spanish scientists took a new step in their knowledge and identified the accumulation of ‘junk proteins’ as a possible origin of the THE A and cause of aging.

The results are published in the journal Molecular Cell by a team led by Óscar Fernández-Capetillo, head of the Genomic Instability Group at the National Cancer Research Center (CNIO), in Spain. The experiments carried out in the research indicate the possible existence of avenues that had not been explored to search for treatments.

The work provides the first evidence that a possible cause of the hereditary type of ALS – familial ALS – is the accumulation in motor neurons of ‘junk proteinsproteins without any function that accumulate improperly and prevent the correct functioning of the cell.

Specifically, these non-functional proteins that accumulate are ribosomal proteins, which normally constitute ribosomes, molecular factories responsible for the production of proteins, explains a statement from the CNIO.

Thus, this study provides a new hypothesis to understand the origin of ALS, by suggesting that it is similar to another group of rare diseases known as ribosomopathies, also associated with an excess of non-functional ribosomal proteins (in the case of ALS, This problem is restricted to motor neurons).

Hereditary and genetic ALS

Most hereditary ALS patients share mutations in a gene called C9ORF72. This mutation results in the production of toxic proteins or peptides rich in the amino acid arginine.

In previous work, Fernández-Capetillo’s group took the first steps to understand why these peptides are toxic. The reason is that these toxins stick to DNA and RNA like ‘tar’, affecting virtually all reactions in the cell that use these nucleic acids.

The study now published shows that the toxin has a particularly acute effect on the manufacture of new ribosomes.

Thus, by not being able to complete its assembly, the cell accumulates an excess of orphan ribosomal proteins, incapable of forming ribosomes, the scientist details. “These proteins end up collapsing the cellular cleaning systems, which ultimately leads to the death of motor neurons.”

Based on this finding, the CNIO group studied solutions. “Since the problem is excess ribosomal garbage, we explored strategies to make cells produce fewer ribosomes.”

To achieve this, they ‘turned off’ two of the ribosome generation mechanisms in tissues ‘in vitro’ with genetic and pharmacological manipulation, proving that, in effect, by producing less ‘garbage’, toxicity is reduced.

These are, however, results that must be interpreted with caution: “We are in the first steps to see if we can give a therapeutic angle to these discoveries. For now, these experiments simply indicate the possible existence of avenues that had not been explored to search for treatments against ALS.”

The challenge is to find ways to reduce the production of ribosomes so that waste is reduced, but ensuring a sufficient number for the correct functioning of the cells.

Causes of aging

The new study also opens a door in a different area, aging research. The authors describe a new causal factor of this process: nucleolar stress, a concept that encompasses the alterations suffered by organelles called nucleoli, responsible for the production of ribosomes.

“In our work we report a new model that explains how nucleolar stress induces toxicity in animal cells and we provide direct evidence that this type of stress accelerates aging in mammals,” says Vanesa Lafarga, co-author of the article.

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