Restoring 'chaperone' protein may prevent plaque build-up in Alzheimer's
Study also shows new role of DAXX protein in tumor suppression

Date:
August 26, 2021
Source:
University of Pennsylvania School of Medicine
Summary:
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.



FULL STORY ==========================================================================
For the first time, Penn Medicine 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 senior author Xiaolu Yang, PhD, a professor of Cancer Biology in
the Perelman School of Medicine at the University of Pennsylvania. "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," Yang said.

The first author of the study is Liangqian Huang, PhD, a postdoctoral researcher in Yang's lab.

This work was supported by National Institutes of Health (R01CA182675, R01CA184867, R01CA235760, R01CA243520, P01 AG031862, and R01GM099836), an Alzheimer's Association Research Fellowship, a Warren Alpert Foundation Distinguished Scholars Fellowship, and a Sponsored Research Agreement
from Wealth Strategy Holding Limited.

========================================================================== Story Source: Materials provided by University_of_Pennsylvania_School_of_Medicine. Note: Content may be
edited for style and length.


========================================================================== Journal Reference:
1. Liangqian Huang, Trisha Agrawal, Guixin Zhu, Sixiang Yu, Liming Tao,
JiaBei Lin, Ronen Marmorstein, James Shorter, Xiaolu Yang. DAXX
represents a new type of protein-folding enabler. Nature, 2021;
DOI: 10.1038/s41586-021-03824-5 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210826111709.htm

--- up 15 weeks, 6 days, 22 hours, 45 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)