For the first time, the researchers showed 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.
The findings were published online 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,” said the senior author. “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.
The researchers showed that DAXX and other polyD/E proteins facilitate the folding of proteins, reverse protein aggregates, and unfold misfolded proteins. They prevent neurodegeneration-associated proteins, such as beta-amyloid and alpha-synuclein from misfolding, tangling, and forming extracellular plaques and intracellular inclusions, they found. Beta-amyloid clumping between the nerve cells is observed in the brains of Alzheimer's disease patients and the target of many treatment approaches, while intracellular inclusions of alpha-synuclein are observed in the brains of patients with Parkinson’s disease.
The team also showed DAXX’s potential role in treating cancer.
DAXX restores native function to tumor-associated and aggregation-prone p53 proteins, reducing their cancer properties. That’s important because p53 is the preeminent tumor suppressor and mutations in p53 are associated with a bevy of cancers, including lung, colon, pancreatic, ovarian, and breast cancer. Bolstering DAXX function, the authors said, might represent an alternative approach to therapeutically reestablish the tumor suppressive function of mutant p53 to treat patients.
“The findings give us a better understanding of a new biochemical activity that effectively contends with protein misfolding seen in Alzheimer’s and other neurodegenerative diseases, as well as in cancer, and represent an opportunity to develop new approaches to treat these diseases,” the author said.
https://www.nature.com/articles/s41586-021-03824-5
A new type of protein folding enabler may prevent plaque build-up in Alzheimer's
- 1,185 views
- Added
Edited
Latest News
Protein that helps COVID-19…
By newseditor
Posted 26 Jul
Spinal Muscular Atrophy (SM…
By newseditor
Posted 26 Jul
Link between bowel movement…
By newseditor
Posted 26 Jul
Inhibition of IL-11 signall…
By newseditor
Posted 25 Jul
Brain changes linked to obe…
By newseditor
Posted 25 Jul
Other Top Stories
Deep-sleep brain waves predict blood sugar control
Read more
Extracellular cytochrome nanowires appear to be ubiquitous in microbes
Read more
Distinct connectivity patterns for depression associated with traum…
Read more
Antisense therapy restores fragile X protein production in human cells
Read more
Biomarker for allergic reaction in kidneys identified!
Read more
Protocols
A systems biology approach…
By newseditor
Posted 24 Jul
quantms: a cloud-based pipe…
By newseditor
Posted 22 Jul
Emerging tools and best pra…
By newseditor
Posted 19 Jul
Directly selecting cell-typ…
By newseditor
Posted 17 Jul
PUFFFIN: an ultra-bright, c…
By newseditor
Posted 16 Jul
Publications
Hepatocyte-intrinsic SMN de…
By newseditor
Posted 26 Jul
Aberrant bowel movement fre…
By newseditor
Posted 26 Jul
A pseudoautosomal glycosyla…
By newseditor
Posted 26 Jul
Microglia protect against a…
By newseditor
Posted 26 Jul
Rigor and reproducibility i…
By newseditor
Posted 26 Jul
Presentations
Myelin plasticity in the ve…
By newseditor
Posted 10 Jun
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar