Protein aggregates are deemed to be one reason for the death of nerve cells in disorders such as Alzheimer’s or Huntington’s disease. As researchers report in the current issue of Nature, they have now decoded a new cellular mechanism for the development of aggregates. Missing stop signals in the production of proteins lead erroneously to long lysine chains at the end of the protein. This in turn blocks the ribosomes, the cell’s protein factory. Healthy cells detect blocked ribosomes and rapidly destroy useless proteins. If the necessary quality control machinery does not function properly, defective proteins accumulate and form toxic aggregates.

In order to be able to treat neurodegenerative disorders in future, researchers have for many years been studying the cellular causes for the death of nerve cells. A determining cause is believed to be protein deposits – aggregates of misfolded proteins.

In each cell, proteins perform vital functions, acting as small molecular machines. The mRNA contains a start signal, the information about the protein structure, a stop signal and, at the end, a poly(A) tail. If the blueprint is damaged, for example due to radiation or mutagenic substances, this can lead to the loss of this stop signal. As a result, once the protein has been manufactured in the ribosomes, the completed protein cannot be released. Instead, the poly(A) tail is interpreted as the blueprint and additional amino acids are attached. The lysine chain that is positively charged as a result blocks the protein factory and the manufacture of protein comes to a standstill.

Healthy cells have a very efficient quality control process when it comes to the manufacture of protein. Misfolded and useless proteins are selected, repaired or rapidly destroyed.

Using a mouse model, the researchers can now demonstrate the fatal consequences of a quality control malfunction. Animals with the relevant mutation show symptoms of advanced neurodegeneration and a restricted ability to move.

The protein aggregates that develop have a sticky surface and act as a seed. They ultimately also bind functioning proteins, which are free of defects and vital for the cell. As a result, the cell is destabilized and, in the long run, is damaged.

Source: Max Planck Institute of Biochemistry


Max Planck Institute of Biochemistry
"Failure of RQC machinery causes protein aggregation and proteotoxic stress"