From The Scientist
December 29, 2003
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 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.
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.
cell.com
Susan Lindquist
the-scientist.com
Eric Kandel
erickandel.org
Nobel Medicine or Physiology Prize 2000
nobel.se
Stanley Prusiner
ucsf.edu
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
umassmed.edu
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
cmpharm.ucsf.edu |
