Findings Could Advance Understanding of Mad Cow Disease,
of Article: http://media-newswire.com/release_1092941.html
at the National Institutes of Health have gained a major insight into
how the rogue protein responsible for mad cow disease and related
neurological illnesses destroys healthy brain tissue.
(Media-Newswire.com) - Scientists at the National Institutes of Health
have gained a major insight into how the rogue protein responsible for
mad cow disease and related neurological illnesses destroys healthy
"This advance sets the stage for future efforts to develop
potential treatments for prion diseases or perhaps to prevent them from
occurring." said Duane Alexander, M.D., Director of NIH’s Eunice
Kennedy Shriver National Institute of Child Health and Human
Development ( NICHD ), where the study was conducted.
The researchers discovered that the protein responsible for these
disorders, known as prion protein ( PrP ), can sometimes wind up in the
wrong part of a cell. When this happens, PrP binds to Mahogunin, a
protein believed to be essential to the survival of some brain cells.
This binding deprives cells in parts of the brain of functional
Mahogunin, causing them to die eventually. The scientists believe this
sequence of events is an important contributor to the characteristic
neurodegeneration of these diseases.
The findings were published in the current issue of the journal Cell.
The study was conducted by Oishee Chakrabarti, Ph.D. and Ramanujan S.
Hegde, M.D., Ph.D., of the NICHD Cell Biology and Metabolism Program.
Central to prion diseases like mad cow disease and to many other
diseases is the phenomenon known as protein misfolding, Dr. Hegde
explained. Proteins are made up of long chains of molecules known as
amino acids. When proteins are created, they must be carefully folded
into distinct configurations. The process of protein folding is
analogous to origami, where a sheet of paper is folded into intricate
shapes. Upon correct folding, proteins are transported to specific
locations within cells where they can perform their various functions.
However, the protein chains sometimes misfold. When this happens, the
incorrectly folded protein takes the wrong shape, cannot function
properly, and as a consequence, is sometimes relegated to a different
part of the cell.
In the case of prion diseases, the culprit protein that misfolds and
causes brain cell damage is PrP. Normally, PrP is found on the surface
of many cells in the body, including in the brain. However, the normal
folding and distribution of PrP can go wrong. If a rogue misfolded
version of PrP enters the body, it can sometimes bind to the normal PrP
and "convert" it into the misfolded form.
This conversion process is what causes mad cow disease, also known as
bovine spongiform encephalopathy. Feed prepared from cattle tissue
containing an abnormally folded form of PrP can infect cows. In very
rare instances, people eating meat from infected cows are thought to
have contracted a similar illness called variant Creutzfeld Jacob
disease ( vCJD ). In other human disorders, genetic errors cause other
abnormal forms of PrP to be produced.
"The protein conversion process has been well studied," Dr.
Hegde said. "But the focus of our laboratory has been on how — and
why — abnormal forms of PrP cause cellular damage."
To investigate this problem, Dr. Hegde’s team has been studying exactly
how, when, and where the cell produces abnormal forms of PrP. They had
found that many of the abnormal forms of PrP were located in the wrong
part of the cell. Rather than being on the cell’s surface, some PrP is
exposed to the cytoplasm, the gelatinous interior of the cell.
Moreover, several studies from Dr. Hegde’s group and others showed that
when too much of a cell’s PrP is exposed to the cytoplasm in laboratory
mice, they develop brain deterioration.
"The sum of these discoveries provided us with a key
insight," Dr. Hegde said. "We realized that in at least some
cases, PrP might be inflicting its damage by interfering with something
in the cytoplasm."
In the current study, Drs. Chakrabarti and Hegde sought to determine
what went wrong when PrP was inappropriately exposed to the cytoplasm.
Their next clue came from a strain of mice with dark mahogany-colored
fur. Although these mice develop normally at first, parts of their
nervous systems deteriorate with age. Upon autopsy, their brains are
riddled with tiny holes, and have the same spongy appearance as the
brains of people and animals that died of prion diseases. The gene that
is defective in this strain of mice is named Mahogunin.
"The similarity in brain pathology between the Mahogunin mutant
mice and that seen in prion diseases suggested to us that there might
be a connection," Dr. Hegde said.
To investigate this possible connection, the researchers first analyzed
PrP and Mahogunin in cells growing in a laboratory dish. When the
researchers introduced altered forms of PrP into the cytoplasm of
cells, they saw that Mahogunin molecules in the cytoplasm bound to the
PrP, forming clusters. This clustering led to damage in the cell that
was very similar to the damage occurring when cells are deprived of
The researchers found that this damage did not occur in the cell
cultures if PrP was confined to the surface of the cell, if the cells
were provided with additional Mahogunin, or if PrP was prevented from
binding to Mahogunin.
The researchers then studied mice with a laboratory induced version of
a human hereditary prion disorder called GSS, or
Gerstmann-Straussler-Scheinker Syndrome. This extremely rare disease
causes progressive neurological deterioration, typically leading to
death between age 40 to 60. Dr. Hegde explained that some GSS mutations
result in a form of PrP that comes in direct contact with the
cytoplasm. In mice that contain one of these mutations, the researchers
discovered that cells in parts of the brain were depleted of Mahogunin.
The researchers did not see this depletion if PrP was engineered to
avoid the cytoplasm.
The findings, Dr. Hedge said, strongly suggest that altered forms of
PrP interfere with Mahogunin to cause some of the neurologic damage
that occurs in prion diseases.
"PrP probably interferes with other proteins too," Dr. Hegde
said. "But our findings strongly suggest that the loss of
Mahogunin is an important factor."
An understanding of how PrP interacts with Mahogunin sets the stage for
additional studies that may find ways to prevent PrP from entering the
cytoplasm, or to replace Mahogunin that has been depleted.
The NICHD sponsors research on development, before and after birth;
maternal, child, and family health; reproductive biology and population
issues; and medical rehabilitation. For more information, visit the
Institute’s Web site at http://www.nichd.nih.gov/.
The National Institutes of Health ( NIH ) — The Nation's Medical
Research Agency — includes 27 Institutes and Centers and is a component
of the U.S. Department of Health and Human Services. It is the primary
federal agency for conducting and supporting basic, clinical and
translational medical research, and it investigates the causes,
treatments, and cures for both common and rare diseases. For more
information about NIH and its programs, visit www.nih.gov.
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