Restoring ‘chaperone’ protein may prevent plaque buildup in Alzheimer’s

For the first time, Penn Medicine researchers have shown how restoring levels of the protein DAXX and a large group of similar proteins prevents the misfolding of the rogue proteins known to drive Alzheimer’s and other neurodegenerative diseases, as well as certain mutations that contribute to cancers. The findings could lead to new targeted approaches that would restore a biological system designed to keep key proteins in check and prevent diseases.

Microscopic image of cancer proteins.
DAXX (red color at top) prevents the aggregation of mutant p53 protein associated with cancers (dark green color at bottom) in cells. (Image: Penn Medicine News)

The findings are published in Nature.

The study focuses on DAXX, or death domain-associated protein, which is a member of a large family of human proteins, each with an unusually high content of two specific amino acid residues, aspartate and glutamate, referred to as polyD/E proteins. The various roles of DAXX and approximately 50 other polyD/E proteins in cell processes have emerged over time, but their role as a protein quality control system—a “chaperone” that directs protein folding, so to speak—was unanticipated.

“We solve a decades-long puzzle by showing this group of proteins actually constitute a major protein quality control system in cells and a never-before-seen enabler of proper folding of various proteins—including misfolding-prone proteins associated with various diseases,” says senior author Xiaolu Yang, a professor of cancer biology in the Perelman School of Medicine. “Keep that family of proteins functioning properly, and the tangling of rogue proteins may be diminished or stopped altogether.”

Proteins are the workhorses of the cell. To ensure normal cellular function and protect against protein-misfolding associated with disease, organisms have evolved elaborate protein quality control systems to enable efficient protein folding. However, these systems, especially those in humans, are still not well understood, which limits the ability to develop effective therapies.

This story is by Caren Begun. Read more at Penn Medicine News.