Controlling Misfolded Proteins in Neurons

In a study published last week in The Embo Journal, researchers identified a protein complex that marks misfolded proteins and directs them toward disposal. The complex is named Linear Ubiquitin Chain Assembly Complex, or Lubac for short. The team is hoping to find a new therapeutic approach to treat neurodegenerative diseases such as Alzheimer’s, Parkinson’s, or Huntington’s chorea, all of which are associated with misfolded proteins.

Earlier studies have revealed that the protein complex Lubac regulates signaling pathways of the innate immune response that are mediated by the transcription factor NF-kB. For example, Lubac can be recruited to trigger immune responses by binding to bacteria in the cells and activating NF-kB.

“Our study revealed that the Lubac system has a previously unknown function,” says senior author Konstanze Winklhofer of Ruhr University Bochum. “It appears that Lubac recognizes misfolded proteins as dangerous and marks them with linear ubiquitin chains, thus rendering them harmless to nerve cells.” Unlike its response to bacteria, this function of Lubac is independent of the transcription factor NF-kB.

Aggregates of misfolded proteins are toxic to cells because they interfere with various processes. For example, these aggregates can have an interactive surface that sequesters and inactivates other essential cellular proteins, leading to disruption of neuronal function and cell death.

The research team decoded the mechanism described above using the huntingtin protein, the misfolding of which causes Huntington’s disease. By attaching linear ubiquitin chains to aggregated huntingtin, the protein aggregates are shielded from unwanted interactions in the cell and can be degraded more easily.

In Huntington’s patients, the Lubac system is impaired. However, the protective effect of Lubac is not limited to huntingtin aggregates. The researchers also detected linear ubiquitin chains attached to protein aggregates that play a role in other neurodegenerative disorders—for example, ALS.

“The attachment of linear ubiquitin chains is a highly specific process, as there is only one protein—namely a Lubac-component—that can mediate it,” Winklhofer explains. “Based on these insights, strategies for new therapeutic approaches could be developed.”

In future studies, the team intends to identify small molecules that affect linear ubiquitination and to test if they have any positive effects on neurodegeneration. But as Winklhofer says, “there is still a long way ahead until a drug can be developed.”