The accumulation of 'junk proteins', cause of aging and possible origin of ALS

THE WORLD Madrid

Madrid

Updated Friday, March 22, 2024-16:04

Amyotrophic lateral sclerosis (ALS) is a degenerative disease. The neurons responsible for movement begin to die and muscle control is progressively lost, until a fatal outcome. Today the causes of ALS are unknown, and there is no efficient treatment. In a work published in

Molecular Cell

, a team led by Óscar Fernández-Capetillo, head of the Genomic Instability Group at the National Cancer Research Center (CNIO), provides the first evidence that a possible cause of the hereditary type of ALS - ALS familiar- is the accumulation in motor neurons of

'junk proteins'

, proteins 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.

Thus, this study provides a

new hypothesis to understand the origin of ALS

, by suggesting that it has a similar origin 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).

The new study also opens a new front in a different area, aging research. The authors describe a new causal factor in the aging 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-corresponding author of the study.

A 'tar' that blocks RNA

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 in Molecular Cell, with Oleksandra Sirozh as first author, shows that the toxin has a particularly acute effect on the manufacture of new ribosomes, production factories within the cell, and which are made up of RNA and proteins.

ALS as ribosomopathy

Thus, by not being able to complete its assembly, "the cell accumulates an excess of orphan ribosomal proteins, incapable of forming ribosomes," explains Fernández Capetillo. "These proteins end up

collapsing cellular cleaning systems,

which ultimately leads to the death of motor neurons."

For the authors, for the first time this work suggests a similarity between the cause of ALS and other types of diseases known as ribosomopathies, also associated with the accumulation of dysfunctional ribosomal proteins in a generalized manner in all cells of the human body.

Based on this finding, the CNIO group has explored a solution. "Since the problem is excess ribosomal garbage, we explore strategies for cells to produce fewer ribosomes," explains Fernández-Capetillo. To achieve this , they turned off

two of the ribosome generation mechanisms in in vitro tissues

with genetic and pharmacological manipulation , verifying that, in effect, by producing less "garbage", toxicity is reduced.

However, Fernández-Capetillo indicates that these results should 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. "We must 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."

A new cause of aging: nucleolar stress

The nucleolus is the cellular component where ribosomes are synthesized. In recent decades it has been observed that one of its functions is also to detect stress situations in the cell, such as DNA damage or lack of nutrients. Nucleolar stress can end up altering protein production, and its triggers are a very active area of ​​research.

In the work now published in

Molecular Cell,

the authors generated animals that express the toxin found in ALS patients throughout the body, which induced strong nucleolar stress. But the researchers also unexpectedly observed that these animals aged very quickly.

'Junk proteins' accelerate aging

Based on their previous studies, they verified that this aging was also due to the accumulation of non-functional ribosomal proteins: thus, when the animals were administered a drug that reduces the rate of ribosome production, their life expectancy doubled.

There had been speculation about the relationship between nucleolar stress and aging, but a causal relationship had not been demonstrated. This work "is the first experimental evidence that shows that

generating nucleolar stress accelerates aging

in an adult mammal," says Fernández Capetillo.

The work has been co-financed by the Ministry of Science, Innovation and Universities, FEDER funds from the European Union, the Spanish Association against Cancer and the "la Caixa" Foundation in alliance with the Francisco Luzón Foundation.