The motor neuron disease ALS: biologists in Bayreuth discover impaired cellular self-cleaning

Amyotrophic lateral sclerosis (ALS) is a disease of the nervous system which remains incurable to this day. It involves the progressive deterioration of the nerve cells responsible for muscle movement. The late British physicist Stephen Hawking suffered from this degenerative disease. An international team of researchers led by the Bayreuth cell biologist Dr. Ralf Braun has now discovered cellular processes that may play a key role in the progression of ALS: the pathogenic protein TDP‑43 interferes with its own breakdown, thus interrupting the self-cleaning of nerve cells. The scientists have published their findings in the journal Human Molecular Genetics.

Protein clumps damage nerve cells

The cytoplasm of nerve cells in humans who suffer from ALS contain numerous clumps of improperly folded proteins. In many cases, they are composed of the protein TDP‑43. In the cell nucleus, this protein is required - among other things - for the transcription of genes. However, it can have pathogenic effects when it accumulates in the cytoplasm.

Dr. Ralf Braun and his research group have now investigated how cells can break down the harmful protein clumps and what kind of impact that has on the cells' survival. The cell biologists in Bayreuth worked together closely with researchers in Graz, Stockholm, and Utrecht. The experiments were carried out on yeast cells, which are recognized as model organisms in basic research in the field of cell biology. The reason is that some key cellular processes are very similar in yeast cells and human nerve cells.

Two pathways of self-cleaning in the cytoplasm

Every nerve cell in human beings and every yeast cell contains organelles that are responsible for digestion. They are known as lysosomes in humans and as vacuoles in yeast. Their purpose is to dispose of or to recycle biomaterial that is harmful or simply unneeded. For elimination of the pathogenic TDP‑43 through lysosomes, they must incorporate these proteins. This mainly occurs in two ways that are also observed in yeast cells:

  • For one thing, protein clumps made of TDP‑43 in the cytoplasm become surrounded by a double membrane. This results in small, spherical structures: the autophagosomes. These fuse with the lysosomes and expose the protein clumps to the enzymes responsible for breaking down TDP‑43.
  • But the cytoplasm also contains multivesicular bodies in which TDP‑43 molecules can become embedded. The multivesicular bodies also fuse with the lysosomes, enabling the breakdown of TDP‑43.

The pathogenic protein TDP43 prevents its own breakdown

The Bayreuth researchers have now identified that a high concentration of TDP‑43 in the cytoplasm interrupts the disposal route that leads through the multivesicular bodies. "We are obviously dealing with a pathogenic protein that prevents its own breakdown. The vacuoles in yeast and the lysosomes in humans cannot fulfil their recycling function effectively," said Christine Leibiger, lead author of the new study.

The researchers suspect that this also limits the disposal of TDP‑43 via autophagosomes. The reason is that multivesicular bodies not only provide the lysosomes with TDP‑43, but also with enzymes that are needed for digestive processes. The researchers hypothesize that as soon as the supply stops working smoothly, the TDP‑43 transported by the autophagosomes can no longer be broken down efficiently either.

Next research steps

"Many research papers addressing the emergence of ALS and the possible therapeutic approaches are mainly interested in the breakdown of TDP‑43 via autophagosomes. In contrast, our study puts the focus on multivesicular bodies, the significance of which may have been underestimated in connection with the self-cleaning powers of nerve cells," explained Dr. Ralf Braun. Together with his research group, he is already planning further experiments based on the findings that were just published. These experiments will be primarily concerned with the question of whether there are enzymes capable of both re-activating the self-cleaning of the cells when weakened by TDP‑43 and making them more robust.

Research Funding:

The study was funded by the German Research Foundation (DFG), the German Society for Muscular Dystrophy (DGM), the Austrian Science Fund (FWF), and the Swedish Research Council.

Full bibliographic information

Christine Leibiger, Jana Deisel, Andreas Aufschnaiter, Stefanie Ambros, Maria Tereshchenko, Bert M Verheijen, Sabrina Büttner, Ralf J Braun: TDP-43 controls lysosomal pathways thereby determining its own clearance and cytotoxicity, Human Molecular Genetics (2018), DOI: 10.1093/hmg/ddy066
Attached files
  • Breakdown of the protein TDP-43 in a human cell / a yeast cell: one pathway routes TDP 43 to the lysosome /to the vacuole leads via autophagosomes, while the other leads through multivesicular bodies. The latter is also involved in the delivery of digestive enzymes into lysosomes. Illustration: Christine Leibiger and Ralf Braun.

Other content in...