International Business Department           Liu Bojia           March 27, 2023

  Inside the nucleus, there is a large membrane-free structure, the nucleolus, which contains hundreds of proteins involved in different functions, and which is important for ribosome biogenesis. As we age, the proteins in the nucleolus become more susceptible to external interference, which can lead to impaired cellular function and inhibit ribosome biogenesis.

  This process of interference, also known as kernel stress, has been significantly associated with neurological disorders, including amyotrophic lateral sclerosis (ALS), commonly known as "acromegaly". The reason for this is that neurons have a much higher need for protein translation, which "affects the whole body", so when problems with the nucleus pulposus lead to ribosomal disorders, neuronal function is significantly impaired.

  For ALS patients, the gradual inactivation of motor neurons after damage is fatal, and patients will eventually lose muscle control and suffer from respiratory failure. However, scientific understanding of acromegaly is still limited, making the development of related therapies extraordinarily difficult.

  In a new paper in Molecular Cell, science from Spain's National Cancer Research Centre has found, for the first time, that the accumulation of "toxic" proteins in motor neurons, mostly ribosomal proteins that, when over-accumulated, inhibit normal cellular function and lead to the development of therapeutic treatments, is a possible cause of ALS. Most of these proteins are ribosomal proteins that, when over-accumulated, inhibit normal cellular function and lead to neuronal collapse.

  Previous studies have found that many people with hereditary ALS carry a mutation in the C9ORF72 gene, which promotes the accumulation of arginine-rich peptide fragments that appear in the nucleolus and progressively impair nucleolus function, leading to cell death.

  In the experiment, the authors introduced a large number of arginine-rich peptides into the cells, and after a period of time the cells developed significant kernel stress, and the cells gradually went to death. According to the analysis, these peptides become an important part of leading cell death, and too many arginine-rich peptides bind to DNA and RNA, which can block all relevant interactions.

  As we may have learnt from textbooks, ribosomes are made up of RNA and proteins, and when RNA is over-occupied, ribosome assembly fails. Therefore the authors observed a large number of free ribosomal proteins in the cell. These ribosomal proteins have no use other than to form ribosomes, and excessive accumulation instead disrupts the cell's waste removal system, ultimately leading to cell death.

  Based on these features, the authors suggest that this also points to some similarities between ALS and ribosomopathy, which is also caused by abnormal accumulation of ribosomal proteins.

  In addition to revealing the underlying mechanisms of ALS, the authors also found in mouse experiments that those mice overexpressing arginine-rich polypeptides not only develop kernel stress, but they also age faster and have a reduced lifespan, suggesting that there is a link between kernel stress and individual aging. In their tests, the authors attempted to use drugs that inhibited ribosomal production and reduced the accumulation of ribosomal proteins, which could return the lifespan of the experimental mice to normal.

  In addition to slowing down aging, targeting the pathway of ribosomal stress and ribosomal protein accumulation may also lead to potential ALS therapies, a previously unexplored direction with considerable potential, the researchers noted. The challenges are still considerable, however, such as the need for the newly developed drugs to reduce ribosome production in a rational way, stopping ribosomal proteins from damaging motor neurons while ensuring the normal ribosome requirements of other cells.