Chicago,
IL (1/28/00)- Prions, the villainous protein-like particles associated
with BSE, also known as "Mad Cow Disease", and its human counterpart,
Creutzfeld-Jakob Disease (CJD), now appear to offer promise as a valuable
tool for molecular biological research.
left: Susan
Lindquist, Ph.D, University of Chicago
Prions are a kind of stray protein found in living tissue. They contain no
nucleic acid (DNA or RNA) of their own. A prion consists of a single molecule
containing about 250 amino acids. They are abnormal variants of proteins that
occur normally in cells, such as human brain cells. When abnormal prions enter
the body, they are able to convert their normal counterparts into more of
the abnormal forms, beginning the process of neuronal cell destruction that
manifests as prion disease. The difference between the normal and abnormal
proteins does not lie in the sequence of their amino acids, but rather in
their folding. The abnormal prion proteins are folded in a way that allows
them to avoid normal protease degradation. As a result they begin to form
clumps or aggregates, literally eating holes in the infected brain.
Now, researchers have shown that these same characteristics that make prions
so dangerous may also be used in the lab to study genes and protein expression.
Working with yeast prions and rat cells, researchers at the University of
Chicago demonstrated a way to attach a prion to a normal protein so as to
give it prion-like characteristics. Moreover, these prions are then passed
on to subsequent generations of cells, while leaving the cells; DNA unchanged.
The researchers alos observed that the misfolded parts of prions, are modular
and can be swapped from one prion to another. The scientists induced the experimental
novel prion to switch from its dysfunctional to its functional state and back
again. This suggests an entirely new method for studying proteins, in which
researchers could study the role of a particular protein by inducing it to
become a prion.
"We've discovered a method to create novel prions which ultimately can have
a lot of applications," said Susan Lindquist, Ph.D., the Albert D. Lasker
professor of molecular genetics & cell biology and Howard Hughes Investigator
at the University of Chicago. "Once the prion part misfolds it entices other
proteins of the same kind to fold incorrectly and they can clump together.
The functional part may still be active. But if its job needs to be done in
a particular place, it can't get there because its stuck."
"The fact that these prion domains proved so modular and transferable, as
revealed in these papers, proved quite a surprise. Since prions such as Sup35
had evolved to have the same general structure for many millions of years,
one might have expected their different domains to have evolved together to
influence one another. This modularity suggests that as species evolved, other
proteins might have picked up these prion domains and become genetic elements.
If they did, this kind of protein inheritance pattern could have had an important
effect on the process of evolution," said Lindquist.
Prions violate the the "central dogma" of biology. All other known life forms
pass along traits via their DNA, or in the case of some viruses, via RNA.
The 'dogma' requires a process involving replication of DNA, transcription
of the message into RNA, and translation of the RNA's message to form proteins,
the building blocks of cells, tissues, organs and whole organisms. Prions,
in contrast, bypass this entire process, direct the refolding of normal proteins
just by direct contact.
The research appeared in the Jan. 28, 2000 issue of Science. A related article
appears in the January 2000 issue of the journal Molecular Cell
Copyright
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