In the (Web) Science News appeared the
following article
FYI: JM
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Good news for prions?
Mad cow and memory: Prion-like proteins proposed to regulate neuronal
plasticity | By Brendan A
Maher
Since their discovery in 1982, prions have been mostly associated with
deadly and devastating neurodegenerative disorders—notably variant
Creutzfeld-Jakob disease and bovine spongiform encephalopathy. Nevertheless,
some maintain that the mechanism by which prions change their shape and
aggregate might be put to good use in biological systems. In back-to-back papers in the December 26 issue of Cell,
researchers ascribe prion-like properties to an elegant mechanism involved
in maintaining memory.
Susan Lindquist, director of the Massachusetts Institute
of Technology's Whitehead Institute, and Eric Kandel, professor of physiology and psychiatry at
Columbia University College of Physicians and Surgeons, describe a protein,
cytoplasmic polyadenylation element-binding protein (CPEB), which appears to
mark active synapses. The protein behaves like a prion in yeast cultures,
and its alternative self-perpetuating form—generally associated with disease
states for other prions—appears to be the protein's active form.
Researchers, in looking to understand memory formation, have struggled to
comprehend how a neuron can strengthen specific synapses while leaving
others alone. Kandel, who shared the 2000 Nobel Prize for work on neuronal signaling, has shown
that protein synthesis, localized to the dendrites, enables a function known
as long-term facilitation, which is a strengthening of synaptic connections
in the large neurons of the sea slug Aplysia californica.
In the Cell papers, he proposes that CPEB maintains that
strengthening process by spurring local translation of ubiquitous but
dormant messages, such as those for structural and regulatory molecules,
which allow a synapse to grow. “It takes sleeping messenger RNAs and it
wakes them up,” Kandel told The Scientist.
Stanley Prusiner, who won the 1997 Nobel Prize for
discovering prions but was not involved in the CPEB work, said in a
statement that the studies represent “a new phase of the prion story.”
First described in maturing Xenopus oocytes, CPEB is highly
conserved in vertebrates and invertebrates, but was thought to be largely
just associated with germ-cell development. Then a human match popped up in
a BLAST search, said molecular medicine professor Joel
Richter, University of Massachusetts School of Medicine in Worcester.
Richter was among the first to describe CPEB's activity. A human match was
not all that surprising, he told The Scientist, “but the source of
the RNA to make the library was kind of interesting. It kind of knocked my
socks off.”
CPEB was found in the human neonatal brain. In 1998, Richter's lab showed
that the protein could be found in post-synaptic regions of mammalian
brains, and suggested that it facilitates polyadenylation and the
translation of proteins associated with synaptic strengthening.
Kandel, postdoc Kausik Si, and other Columbia colleagues eventually
showed that a number of serotonin pulses, designed to simulate the kind of
training that leads to long-term memory, upregulated a neuronal isoform of
Aplysia CPEB at the synapse. When blocked, facilitation faded,
suggesting that CPEB is a stabilizing component for long-term facilitation.
In this neuronal isoform, Si noticed a glutamine and asparagine rich
N-terminus—a characteristic common to yeast prions, said Kandel. “Prion
domains endow proteins with the ability to be self-perpetuating, and he
said, 'Wow, wouldn't it be nifty if this CPEB protein is
self-perpetuating?'” Such properties, the researchers reasoned, could allow
memory storage over a lifetime. So Kandel's group worked with Lindquist to
determine if the protein, in yeast, displayed prion-like properties under
the right conditions. They found, through a number of assays, that a
dominant conformational change in CPEB was transmissible among cell lines,
and was actually an active form of the protein that could bind and
polyadenylate mRNA containing the right sequence.
“It would be a relatively low-energy way of doing long-term memory,” Fred
Cohen, professor of cellular and molecular pharmacology at the
University of California, San Francisco, told The Scientist. “If you
had to always phosphorylate a set of proteins to maintain a memory, then
you're constantly spending energy to do that.”
But the groups have yet to show that the protein exists in more than one
conformational state in Aplysia synapses. Such a demonstration will
begin to illustrate whether a self-perpetuating mechanism might regulate
long-term memory. And even if the mechanism exists in Aplysia, it may
not be the same as in vertebrate systems. Vertebrate CPEB proteins don't
have the same glutamine rich sequences, and they have phosphorylation sites,
suggesting an alternative mechanism.
“Maybe the prion is more invertebrate like, and the phosphorylation is
more vertebrate like. …That's conjecture, but it's approachable
experimentally,” said Richter, who has been collaborating with Kandel to
study rodent models for CPEB regulation.
But Lindquist told The Scientist that such differences might not
matter much for a mechanism she believes is used in many biological systems.
“We think that it's not only Q-rich sequences that are capable of these
conformational changes, and in fact the founding member—the mammalian prion
[PrP]—is not particularly glutamine-rich.”
Links for this articleS.B. Prusiner, “Novel proteinaceous infectious particles cause
scrapie,”
Science, 216:136-44, 1982.
[
PubMed
Abstract]
K. Si, et al., “A neuronal
isoform of the
Aplysia CPEB has prion-like properties,”
Cell,
115:879-91, Dec. 26, 2003.
http://www.cell.com/ K. Si et
al., “A neuronal isoform of CPEB regulates local protein synthesis and
stabilizes synapse-specific long-term facilitation in
Aplysia,”
Cell, 115:893-904, December 26, 2003.
http://www.cell.com/ Susan
Lindquist
http://www.the-scientist.com/yr2003/feb/upfront4_030210.html Eric Kandel
http://www.erickandel.org/erickandel/members_fr.html Nobel Medicine or Physiology Prize 2000
http://www.nobel.se/medicine/laureates/2000/index.html Stanley Prusiner
http://www.ucsf.edu/neurosc/faculty/neuro_prusiner.html L.L. McGrew et al., “Poly(A) Elongation during
Xenopus
oocyte maturation is required for translational recruitment and is mediated
by a short sequence element,”
Genes Dev, 3:803-15, 1989.
[
PubMed
Abstract]
Joel Richter
http://www.umassmed.edu/igp/faculty/richter.cfm L. Wu et al., “CPEB-mediated cytoplasmic polyadenylation and
the regulation of experience-dependent translation of alpha-CaMKII mRNA at
synapses.”
Neuron, 21:936-8, 1998.
[
PubMed
Abstract]
Fred Cohen
http://www.cmpharm.ucsf.edu/cohen/welcome.html
©2003, The Scientist Inc. in association with BioMed
Central.
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And another one from an Ukranian
outfit:
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----- Original Message -----
Sent: Monday, December 29, 2003 12:04 PM
Subject: [postpsychology] 'Mad Cow' Mechanism May Be Integral To
Storing Memory
'Mad Cow' Mechanism May Be Integral To Storing
Memory
CAMBRIDGE, Mass. (Dec. 24, 2003) – Scientists have discovered
a new process for how memories might be stored, a finding that could help
explain one of the least-understood activities of the brain. What's more,
the key player in this process is a protein that acts just like a prion – a
class of proteins that includes the deadly agents involved in
neurodegenerative conditions such as mad cow disease.
The study, published as two papers in the Dec. 26 issue of the journal
Cell, suggests that this protein does its good work while in a prion state,
contradicting a widely held belief that a protein that has prion activity is
toxic or at least doesn't function properly.
"For a while we've known quite a bit about how memory works, but we've
had no clear concept of what the key storage device is," says Whitehead
Institute for Biomedical Research Director Susan Lindquist, who coauthored
the study with neurobiologist Eric Kandel at Columbia University. "This
study suggests what the storage device might be – but it's such a surprising
suggestion to find that a prion-like activity may be involved."
Central to a protein's function is its shape, and most proteins maintain
only one shape throughout their lifetime. Prions, on the other hand, are
proteins that can suddenly alter their shape, or misfold. But more than just
misfolding themselves, they influence other proteins of the same type to do
the same. In all known cases, the proteins in these misfolded clusters cease
their normal function and either die or are deadly to the cell – and
ultimately to the organism.
For this reason, Kausik Si, a postdoc in Kandel's lab, was surprised to
find that a protein related to maintaining long-term memory contained
certain distinct prion signatures. The protein, CPEB, resides in
central-nervous-system synapses, the junctions that connect neurons in the
brain. Memories are contained within that intricate network of approximately
1 trillion neurons and their synapses. With experience and learning, new
junctions form and others are strengthened. CPEB synthesizes proteins that
strengthen such synapses as memories are formed, enabling the synapses to
retain those memories over long periods.
For the study, the team extracted the CPEB protein from a sea slug. This
lowly creature has achieved high status in neurobiology because its neurons
are so big, they can be manipulated and turned into unusually powerful
investigative tools. The researchers fused this CPEB to other proteins that
would serve as reporters of activity, and then observed its behavior in a
variety of yeast models. The researchers discovered that CPEB altered its
form and caused other proteins to follow – functioning exactly like a prion.
A second unexpected finding was that CPEB carried out its normal function –
protein synthesis – when it was in its prion state.
"This is remarkable not just because the protein executes a positive
function in its prion-like state," says Lindquist. "It also indicates that
prions aren't just oddballs of nature but might participate in fundamental
processes."
The finding contradicts the notion that converting to a prion state is a
bad thing, says Kandel. "We show instead that the normal state of CPEB may
be the less active state, and the prion state may be the effective way of
utilizing the normal function of the protein."
The work suggests it's possible that in mammalian neuronal synapses,
CPEB's prion properties may be the mechanism that enables the synapses and
nerve cells to store long-term memory, a theory the researchers plan to
investigate next. Theoretically at least, prions are perfect for this, says
Lindquist. Prions could shift into this state quickly without the
energy-intensive cellular mechanics that fuel most protein synthesis. The
prion state is very stable and can maintain itself for months, even years.
But, "We still need to demonstrate that this prion mechanism operates not
just in yeast but in neuron cells," says Kandel.
Lindquist believes that these findings will not be the last time prions
are discovered to have normal biological roles. In fact, she has long
speculated that researchers will discover them to be essential to many
cellular functions. Kandel adds that he wouldn't be surprised if this sort
of prion mechanism was discovered in areas such as cancer maintenance and
even organ development.
Editor's Note: The original news release can be found here.
This story has been adapted from a news release issued by Whitehead
Institute For Biomedical
Research