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The stop codon protects the cell from toxic protein aggregates

LifeSciencesToday based on the materials of Max-Planck-Institut für Biochemie: Stop signals against protein clumps

Whether it's Alzheimer's disease or Huntington's disease, protein aggregates are considered the cause of nerve cell death. Scientists from the Max Planck Institute of Biochemistry in Martinsried have deciphered the cellular mechanism that explains the formation of these aggregates. The loss of stop signals leads to the formation of long lysine chains at the end of synthesized proteins. Because of this, the cellular "factory" for the production of proteins – the ribosome - is blocked. Healthy cells recognize blocked ribosomes and quickly destroy useless proteins. If the necessary control over the quality of proteins does not work, defective proteins accumulate and form toxic aggregates.

For the treatment of neurodegenerative diseases in the future, the head of the Cell Biochemistry department of the Max Planck Institute of Biochemistry, Professor Franz-Ulrich Hartl and his group have been studying the causes of nerve cell death for many years. The decisive reason is recognized as protein aggregates – clusters of improperly folded proteins.

"We have shown that errors in the protein construction instructions contribute to the formation of aggregates if they are not detected by internal quality control," comments the results of the study by Young–Jun Choe, the first author of the article Failure of RQC machinery causes protein aggregation and proteotoxic stress published in the journal Nature.

In every cell, proteins–small molecular machines–take on vital functions.

"DNA can be thought of as a huge library of protein assembly instructions located in the nucleus. To form a protein, a copy of the instruction is first made – matrix RNA. This copy is then transferred from the nucleus to the ribosomes, which build a protein from amino acids," explains Choe.

Matrix RNA contains a starting signal, information about the structure of the protein, a stop codon and at the end the so-called poly-A-tail. If the nucleotide sequence is damaged, for example, by radiation or mutagenic substances, the stop signal may be lost. In this case, the finished protein does not exit the ribosome, but the poly-A tail is interpreted as a construction instruction, which is why additional amino acids are added to the protein. The resulting positively charged lysine chain blocks the protein factory, and protein synthesis stops.

In healthy cells, highly effective control over the quality of protein construction is carried out. Improperly folded and useless proteins are marked, repaired or quickly dismantled. An important part of quality control is the Ltn1p protein.

Whether Ltn1p is inactive in pathologically altered cells or there are no other quality control components, defective proteins accumulate inside the cell and stick together.

If the instructions for protein synthesis (matrix RNA) are damaged, proteins useless for the cell are built in ribosomes. Without control over their quality, they accumulate and form aggregates (diagram from an article in Nature).

What can be the fatal consequences of damage to quality control has already been shown in a mouse model. Animals with the corresponding mutation show symptoms of progressive neurodegeneration and physical disability.

The resulting protein aggregates have the property of stickiness and act as nuclei of crystallization. In the end, they bind both properly folded and vital proteins for the cell. In the long run, the cell gets seriously damaged.

"It is interesting that the cell in this case follows an already known model," says Professor Hartl. "We already know that protein aggregates bind vital error-free proteins from previous studies of the huntingtin protein. This protein self–organizes into clots and is responsible for the development of a neurodegenerative disease in humans - Huntington's disease."

"Having obtained these results, we not only demonstrated a possible mechanism for the development of neurodegenerative diseases, but also found another example of how proteins stick together into aggregates and can damage the cell. This confirms our assumption that the suppression of the aggregation process is a promising therapeutic approach to the treatment of a large number of incurable neurodegenerative diseases today," Professor Hartl summarizes the results of the study.

Portal "Eternal youth" http://vechnayamolodost.ru  11.03.2015