prion

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 article
S.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

----- Original Message -----

From: Yuri Bessarab

To: *** Com

Sent: Monday, December 29, 2003 12:04 PM

Subject: [postpsychology] 'Mad Cow' Mechanism May Be Integral To Storing Memory

Source:

Whitehead Institute For Biomedical Research

Date:

2003-12-29

'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

prion

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