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From: ScienceDaily (1:317/3)
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Date: Tue, 20.10.20 23:30
The road to uncovering a novel mechanism
The road to uncovering a novel mechanism for disposing of misfolded

October 20, 2020
Baylor College of Medicine
The discovery of the cause of a rare liver disease in babies led to
uncovering a novel cellular mechanism for disposing of misfolded
proteins that has implications for neurodegenerative conditions
of older age.

About 30 years ago, Dr. Richard Sifers set out on a journey to
discover why people with a rare condition known as alpha1-antitrypsin
(AAT) deficiency present with high variation in the severity of
liver disease. His journey led him to the discovery of fundamental
underpinnings of this condition and, unexpectedly, to uncovering a
novel cellular mechanism for disposing of misfolded proteins. The latter
has implications not just for AAT-deficiency, but also for other more
common conditions associated with accumulation of defective proteins,
including neurological disorders, such as Alzheimer's disease.

AAT deficiency can develop in people who carry the AAT gene with a
mutation called Z.

"I began studying AAT deficiency because I was intrigued by the wide
range of severity of the condition. Some of the people carrying two
copies of the Z mutation developed lung disease late in life and some
developed liver disease.

Interestingly, the condition also could appear very early in life. Some
newborns and infants developed severe liver disease and needed to have
a transplant to live," said Sifers, professor of pathology & immunology
and member of the Dan L Duncan Comprehensive Cancer Center at Baylor
College of Medicine.

Other groups had shown that about 1 in 1,700 people carry two copies of
the AAT-Z gene. However, only about 17 percent of these newborns with
AAT-Z had clinically significant liver disease, and less than 3 percent
of those progressed to life-threatening, end-stage disease as infants.

One of Sifers's first contributions was to help develop the first
screening test to determine whether a newborn was at risk of developing
severe liver disease.

"Developing the screening method made me realize that I could tell
whether a child was at a high risk of having liver disease, but still
did not know what was causing the condition," Sifers said.

Understanding AAT-deficiency AAT is a protein produced by the liver and
transported through the blood to the lungs, where it protects them from
damage caused by other enzymes that breakdown proteins in the lung. The
Z mutation produces a defective AAT protein that cannot fold into an
appropriate 3-D conformation. Inappropriately folded AAT-Z proteins cannot
exit the liver, so they do not travel to the lungs to protect them from
destruction. This can lead to lung damage contributing to emphysema and
other lung conditions.

"As I studied the disease, I noticed that AAT-Z, which should be released
from the liver, was actually accumulating," Sifers said. "This suggested
that the naturally disposing mechanism of the cell might not be working."
Sifers and others dug deeper into how cells dispose of misfolded
proteins. They discovered that cells shuttle defective proteins from
their place of synthesis, the endoplasmic reticulum (ER), to the cytosol,
where they are degraded in a cellular structure called a proteasome. Key
to this process is to tag the proteins for destruction.

"We showed that removing certain sugars from proteins would flag
them for degradation," Sifers said. "Specifically, we found that the
human enzyme mannosidase Man1b1 acted like a quality-control factor
that mediated the removal of the sugar mannose from misfolded AAT-Z
proteins, promoting their degradation." The AAT deficiency model has
been used by many other researchers studying conditions also linked to
toxic accumulation of misfolded proteins in cells, altogether called
conformational diseases. This approach has accelerated the understanding
of the underlying causes of these conditions, offering novel opportunities
for potential treatments.

Connecting Man1b1 and AAT deficiency-associated liver disease in infants
Although researchers knew that liver injury associated with AAT deficiency
was linked to accumulation of misfolded AAT-Z proteins in the liver,
there was still no explanation for the severe liver disease in infants.

In a 2009 paper, Sifers and his colleagues studied liver tissue samples
from unrelated infants or children older than 2 years who had undergone
liver transplantation for end-stage liver disease. They also conducted
genetic linkage and functional laboratory experiments with other cells
cultured in the lab.

They showed that certain genetic modification, a single nucleotide
polymorphism, that leads to changes in the expression of the Man1b1 gene
results in lower levels of Man1b1protein in the endoplasmic reticulum
of liver cells.

Sifers and colleagues proposed that lower levels of Man1b1 impair the
liver's capacity to deal with the accumulation of misfolded AAT-Z. This
likely accelerates reaching the tolerable threshold for protein
accumulation, resulting in earlier liver failure.

Having AAT-Z and a genetic variant that slows down the disposal of
misfolded AAT-Z proteins can explain the condition in the youngest

"I was delighted that after years of research, we had found an explanation
for the mystery of AAT deficiency-associated liver disease in infants
and wondered whether my lab would make other major contributions in the
future," Sifers said.

Man1b1 has more than one role As Sifers and colleagues continued studying
Man1b1, they unexpectedly came across a role for this protein that had
not been described before.

"We found that, in addition to tagging misfolded proteins for degradation
by enzymatically removing mannose groups, Man1b1 also promotes protein
degradation by another mechanism that is independent from the first,"
Sifers said.

Sifers and his co-authors, Dr. Ashlee H. Sun, now at Polypus-transfection
Biotechnology, and Dr. John R. Collette, postdocs in his lab, reported
in the Proceedings of the National Academy of Sciences, that the
conventional enzymatic removal system resides in one side of Man1b1,
the C-terminal domain.

In contrast, the new unconventional system is controlled by the other
side of Man1b1, the N-terminal domain. Further studies will elucidate
whether and how both systems operate in synergy.

The researchers propose that the new unconventional system might be
involved in the elimination of soluble protein aggregates that have
been associated with conformational diseases. For instance, human
Man1b1 has been linked to the causes of multiple congenital disorders
of intellectual disability and HIV infection, and to poor prognosis in
patients with bladder cancer.

"Our work is a clear example that studying rare diseases can bring
solutions for more common conditions." By investigating a rare liver
disease in babies, we have stumbled upon a pathway that could possibly
be targeted to prevent more common neurological disorders occurring in
late age," Sifers said.

This study was supported by research grants from Alpha-1 Foundation.

Story Source: Materials provided by Baylor_College_of_Medicine. Original
written by Ana Mari'a Rodri'guez, Ph.D.. Note: Content may be edited
for style and length.

Journal Reference:
1. Ashlee H. Sun, John R. Collette, Richard N. Sifers. The cytoplasmic
of human mannosidase Man1b1 contributes to catalysis-independent
quality control of misfolded alpha1-antitrypsin. Proceedings
of the National Academy of Sciences, 2020; 117 (40): 24825 DOI:

Link to news story:

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