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From: TSS ()
Subject: Scientists Observe Infectious Prion Proteins Invade and Move Within Brain Cells
Date: May 28, 2005 at 11:16 am PST

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Scientists Observe Infectious Prion Proteins Invade and Move Within Brain

Scientists for the first time have watched agents of brain-wasting diseases,
called transmissible spongiform encephalopathies (TSE), as they invade a
nerve cell and then travel along wire-like circuits to points of contact
with other cells. These findings will help scientists better understand TSE
diseases and may lead to ways to prevent or minimize their effects. TSE, or
prion, diseases include scrapie in sheep and goats; chronic wasting disease
in deer and elk; mad cow disease in cattle; and Creutzfeldt-Jacob disease in

Under the direction of Byron Caughey, Ph.D., at the Rocky Mountain
Laboratories (RML) and Marco Prado, Ph.D. at the University of Minas Gerais
in Belo Horizonte, Brazil, the team performed the research in laboratory
cultures using a rodent-adapted form of scrapie protein and cells taken from
the central nervous system of mouse and hamster brains. The proteins were
first "branded" with fluorescent dyes so they could be easily tracked.

The work also revealed that a similar trafficking process might occur with
the key plaque-forming protein in Alzheimer's disease, which is not a TSE
but a different type of degenerative brain disease, according to Gerald
Baron, Ph.D., one of the lead RML researchers. RML, located in Hamilton, MT,
is part of the National Institute of Allergy and Infectious Diseases (NIAID)
of the National Institutes of Health. The new report appears in the May 25
issue of The Journal of Neuroscience.

"These findings offer intriguing leads toward developing therapies to stop
the spread of TSE and possibly other degenerative brain diseases," says
NIAID Director Dr. Anthony Fauci. "Potentially, it may be possible to block
the pathways that prions use to invade cells, their exit to other cells or
their replication within the cells."

Those are precisely some of the next experiments the RML group is pursuing,
along with trying to move the fluorescent tracking method from laboratory
cell cultures to live mice and hamsters. Along with Drs. Caughey, Prado and
Baron, other key researchers involved in the project included Kil Sun Lee,
Ph.D., RML, and former RML employee Ana Cristina Magalhães, Ph.D., also from
the Federal University of Minas Gerais. Dr. Baron explains that throughout
his seven years at RML, he and others have contemplated how to use
fluorescent tracking to learn more about TSEs, but they struggled to develop
an effective method to do so.

"When I started working on TSEs, I thought about them as being similar to
intracellular bacterial pathogens - something that replicates within an
animal or human host cell," says Dr. Baron. "I wanted to know how such a
pathogen binds to the host cell, and how it enters, replicates and spreads
to other cells."

Dr. Baron says researchers have tracked infectious prion protein moving
through other parts of animal bodies up to the brain, but no one had ever
tracked the protein movement within animal brain cells. One of the most
difficult aspects of the experiment, he says, was finding a way to
fluorescently tag the TSE prion proteins without altering them - while still
allowing researchers to identify the prions as they penetrated the cells and
spread within the long projections that nerve cells develop to send signals
to other nerve cells.

"This was difficult from a technical aspect because the scrapie pathogen is
largely a corrupted form of a host cell protein," Dr. Baron said. "It can be
hard to detect the corrupted prion protein in living infected cells and
distinguish it from its normal counterpart."

He explains that once researchers learned how to mark the prion proteins,
they added them to a culture of nerve cells and then began watching and
taking photo images with a confocal microscope. Confocal microscopy uses
laser light to scan many thin sections of a fluorescent sample, resulting in
a clean three-dimensional image. The painstaking job of analyzing and
deciphering about 1,000 different images primarily belonged to Dr.
Magalhães - who filled a file cabinet drawer with CDs containing microscopic
images. The effort resulted in striking photos that, when put into a video
format, show prion protein moving within cells, then along narrow cellular
projections called neurites and ultimately into close proximity with
adjacent cells.

Other areas the research group plans to explore include:

Exactly where within nerve cells does scrapie infection occur, and how does
this happen?
How and why do large masses of infectious prion protein attach to host cells
and become broken into smaller units so that they can invade the cell
What types of chemical messages are sent between neurites from one cell to
another that allow infectious prions to transfer between cells?
What happens to the infectious prion protein once it is transferred to
another cell?
How do the many different possible pathways that lead into cells determine
what happens to prion protein; some pathways could lead to digestion by the
cell, others lead to transfer - and presumably infection - in adjacent
"This has been pretty amazing - certainly a new approach for our field," Dr.
Baron says.

NIAID is a component of the National Institutes of Health, an agency of the
U.S. Department of Health and Human Services. NIAID supports basic and
applied research to prevent, diagnose and treat infectious diseases such as
HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis,
malaria and illness from potential agents of bioterrorism. NIAID also
supports research on transplantation and immune-related illnesses, including
autoimmune disorders, asthma and allergies.

News releases, fact sheets and other NIAID-related materials are available
on the NIAID Web site at
Reference: A Magalhães et al. Uptake and neuritic transport of scrapie prion
protein coincident with infection of neuronal cells. The Journal of
Neuroscience 25 (21):5207-16 (2005). DOI: 10.1523/JNEUROSCI.0653-05.2005.


----- Original Message -----
From: "Terry S. Singeltary Sr."
Sent: Saturday, May 28, 2005 6:55 AM
Subject: Scientists Observe Infectious Prion Proteins Invade and Move Within
Brain Cells

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