Researchers know that Huntington's disease is driven by a single mutated gene that creates proteins with abnormally long repeats of an amino acid, but the steps that kick off the process of cell damage and death have long remained a mystery. Now investigators report that the discovery of a mechanism driven by misfolded proteins could be one early trigger for cell death.
Scientists using mouse striatal cells and rat cells that model neurons have revealed that the amino acid glutamine (Q) causes proteins (polyQ-expanded) in certain neurons to misfold and clump together, damaging and eventually killing the cells.
The team found that cells generated with polyQ-expanded fragments quickly showed problems with proteins that had been marked for degradation in the endoplasmic reticulum (ER). Such proteins were not expelled for tagging and degradation in the cytosol outside the ER.
“With no garbage disposal, all of a sudden the ER is flooded with proteins that need to be degraded,” said Martin Duennwald, Ph.D., a principal scientist at Boston Biomedical Research Institute.
The group also uncovered the basis for the breakdown. PolyQ-expanded fragments glom onto the key VCP/Npl4/Ufd1 protein complex that aids in the transport and degradation of the proteins that flunk quality control in the ER.
When the investigators modified cells to overexpress two crucial proteins in the protein complex, the toxic effect dropped.
Additionally, the experiments showed that polyQ-expanded proteins avoid a main method by which cells deal with misfolded proteins. Generally, a class of proteins called heat shock proteins move in and either help the misfolded proteins assume their normal shape or help to get rid of them. “Amazingly, polyQ-expanded proteins don’t elicit the heat shock response, and that might contribute to their toxicity,” said Dr. Duennwald.
The article appears online November 17 in Genes & Development, Scientists from Boston Biomedical Research Institute and Howard Hughes Medical Institute worked on the study.