Why do nerve cells die

Protein aggregates disrupt transport in the cytoplasm

LifeSciencesToday based on the materials of Max Planck Society: Why nerve cells die

In the brain cells of patients with neurodegenerative diseases, doctors and scientists see protein clusters under the microscope, they are also protein aggregates. The fact that these aggregates contribute greatly to the death of nerve cells and to the development of diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis has been assumed for many years. A group of scientists led by Mark Hipp and Ulrich Hartl from the Max-Planck-Institut für Biochemie in Martinsried has shown that the survival of cells is greatly influenced by their location. If accumulations in the nucleus practically do not affect its functions, then protein aggregates located in the cytoplasm disrupt important transport routes between the cytoplasm and the nucleus: proteins and RNA in this case cannot be transported to (or from) the nucleus.

Proteins consist of long amino acid chains and function in cells as small mechanisms. In order to do its job, the protein must form a certain predetermined three-dimensional structure. Healthy cells are helped by a lot of "improvised" in the proper folding of protein molecules. In addition, they have a comprehensive quality control system. Improperly folded proteins are either repaired or quickly disassembled into their component parts. If this did not happen, or it would happen to an insufficient extent, proteins, interacting with similar to themselves or other proteins, would form aggregates and damage cells.

However, exactly how protein accumulations damage cells remains unclear today. Therefore, in 2013, the ToPAG-Konsortium consortium organized the cooperation of several groups of specialists of different profiles in order to solve this riddle. Now researchers can present the first results of their research. Thus, scientists from the laboratory of Dr. Ulrich Hartl, a world-renowned expert in the field of protein folding, have shown that cell survival depends crucially on the location of protein aggregates.

To come to such conclusions, Dr. Hartl and his colleagues, in collaboration with scientists from the Ruhr University in Bochum (Ruhr-Universität Bochum), tested an artificially created protein and mutant huntingtin responsible for the development of Huntington's disease on cell cultures. Both proteins self-organized into large aggregates.

"It is interesting that both of these proteins formed more soluble (and more toxic to the cell) aggregates in the cytoplasm than in the cell nucleus," comments the results of the experiments, the head of the study, Dr. Hipp.

Protein aggregates are apparently responsible for the death of nerve cells in neurodegenerative diseases - Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease. In order for the protein aggregates (red) in the cells to be seen in a microscope, they need to be pre-colored. In the picture, the nuclei of cells are blue, the mRNA matrices for the formation of proteins are green. (Photo: MPI für Biochemie)

Protein aggregates in the cytoplasm disrupt the transport of RNA and properly folded proteins between the nucleus and the cytoplasm. Since aggregates have the property of stickiness, the cell is deprived of vital proteins.

"In the aggregates located in the cytoplasm, we found important components of cellular transport machinery. This, in all likelihood, leads to the fact that there are not enough components for the functioning of the intra-core transport, something similar to the absence of certain parts in the car. In this case, it eventually fails too. Presumably, this is the cause of damage to transport routes. If the matrix for building a protein – RNA – cannot get from the nucleus to the cytoplasm, proteins can no longer be built in the cell, and the cell dies," explains Andreas Wörner, the first author of the study.

Why nerve cells are damaged to a lesser extent if the aggregates are located directly in the nucleus can only be assumed. According to the study, the nuclear protein NPM1 seems to play a key protective role here.

"For us, scientists and doctors, the results of this study are a big step forward," Dr. Hipp sums up. "Because when we know what harm the aggregates cause, we will be able to develop appropriate countermeasures in the future."

Article by Woerner et al. Cytoplasmic protein aggregates interfere with nucleo-cytoplasmic transport of protein and RNA published in the journal Science. 

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