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 brain
"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
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
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
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
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 Mahogunin.
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
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/.
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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.