Fwd: [>Htech] theloom: memories stored by prions?

jbone at place.org jbone at place.org
Mon Jan 5 10:12:16 PST 2004


FYI, for those not on the various lists...

jb

Begin forwarded message:

> From: Alejandro Dubrovsky <alito at organicrobot.com>
> Date: Sat Jan 3, 2004  06:59:20 US/Central
> To: transhumantech <transhumantech at yahoogroups.com>
> Subject: [>Htech] theloom:  memories stored by prions?
> Reply-To: transhumantech at yahoogroups.com
>
> (
> http://www.corante.com/loom/archives/001005.html
> and below that
> http://www.eurekalert.org/pub_releases/2003-12/wifb-cm121703.php
> )
>
> Mad Cow Memories
> I can already see the grim look many Americans will have as they chew  
> on
> their Christmas roast tomorrow. They'll be thinking about yesterday's
> report that a cow in Washington state tested positive for mad cow
> disease. There's some comfort in knowing that so far it's just a single
> cow, and that American cattle are regularly screened for bovine
> spongiform encephalitis. The grimmest look this Christmas may be on the
> faces of McDonald's shareholders and cattle ranchers. A single Canadian
> cow that test positive wreaked havoc on the entire beef industry up
> north. But this Christmas also brings a fascinating discovery (((posted
> below))) about the bizarre agents that cause disorders such as mad cow
> disease: they may actually record our memories.
>
> The work comes from the lab of Eric Kandel, the Columbia University
> neuroscientist who won the 2000 Nobel Prize for medicine. Kandel got  
> the
> prize for figuring out some of the molecular underpinnings of memories.
> Each neuron has one set of branches that send outgoing signals and
> another set that receives incoming ones. These signals can only jump
> from one neuron to the next if an outgoing branch nuzzles up to an
> incoming one, creating a junction called a synapse. Kandel studied how
> the neurons in a sea slug change as memories are laid down. (These are
> obviously not memories of the Proustian sort--just simple associations,
> such as the memory of a shock coming after the flash of a light.) He
> showed that new synapses are created and other ones grow stronger as
> memories form. Kandel also identified a number of the molecules that
> seem to be responsible for strengthening these connection. (HisNobel
> prize lecture makes for good reading.)
>
> Kandel did not rest on his laurels, but immediately tackled some of the
> big questions about memory that he and other neuroscientists had yet to
> figure out. A neuron may have tens of thousands of synapses, but only a
> few of them may change as a memory forms. Yet the instructions to make
> proteins that cause this change come from a neuron's single bundle of
> DNA. If the nucleus gets a signal to form new synapse-strengthening
> proteins, how do the proteins go only to the right synapses. And, even
> more importantly, how do those synapses stay strong for decades, when
> proteins themselves live only a short period of time?
>
> Kandel and his coworkers reasoned that a memory-forming synapse must  
> get
> some sort of "synaptic mark" that tagged it for synapse-strengthening
> proteins. They then looked for molecules that might be responsible for
> the mark. As they report in the December 26 issue of Cell, they have
> discovered what may well be the synaptic mark in a compound called
> cytoplasmic polyadenylation element binding protein (CPEB for short).
> CPEB can be found in cells throughout the body, but they found a  
> special
> form of it in the neurons of sea slugs, and then later found it in  
> fruit
> flies and mammals. They found that CPEB is synthesized during the
> earliest stages of memory formation, and probably drives the production
> of molecules that physically lay down new synapses and tells them where
> to grow. Evidence suggests that the protein can do this by "waking up"
> dormant RNA molecules in the synapse. (RNA is the messenger molecule
> that carries copies of genetic information to the protein-building
> factories of the gene.)
>
> To understand how CPEB could do all this, the researchers looked  
> closely
> at its structure. That's when they had a shock: CPEB has much the same
> structure as the agent that causes mad cow disease.
>
> Mad cow disease is infectious, but it's caused not by a virus or a
> bacterium. Instead, it's caused by a rogue protein called a prion. The
> normal version of the protein (called PrP) may do a number of jobs in
> the body, and seems particularly important in the brain. But sometimes  
> a
> PrP gets a funny kink in it and folds into a new shape. This new prion
> then bumps into a normal PrP and forces the normal copy to take on its
> own strange shape. The prions clump together and force others to join
> them in Borg-like fashion. Mad cow disease can spread if cows eat feed
> that has been supplemented with other cows--in particular, if the feed
> contains prions. Humans eating those sick cows can take in the prions  
> as
> well and get a fatal brain disease of their own called Creutzfeld-Jacob
> disease.
>
> Prions were the object of scorn and skepticism for years, in part
> because they were so different as pathogens from viruses or bacteria.
> Prions had no genetic material, and yet they spread like
> genetically-based pathogens. Eventually the evidence became too much to
> ignore (and also won Stanely Prusiner of the University of California  
> at
> San Francisco a Nobel of his own). But prions were revolutionary in
> another way that most people don't know about: they enjoy a unique kind
> of evolution.
>
> In the early 1990s scientists realized that yeast contain prions. These
> aren't mutant PrPs, however, but two completely different proteins that
> just so happen to have the ability to change shape and force other
> proteins to clump with them. Unlike mad cow prions, yeast prions don't
> necessarily harm their hosts--in fact, they actually make yeasts thrive
> better than without them. And since yeasts are single-celled, they can
> pass down their prions to their offspring. (A prion in your brain won't
> get down to your sperm or eggs, so you can't infect your kids.)
>
> In other words, a yeast can inherit prions from its parents, despite  
> the
> fact that it has inherited no prion gene. This non-DNA based  
> inheritance
> is a lot more like what Lamarck was talking about than Darwin.
>
> Kandel and his Columbia team joined forces with an expert on prions in
> yeast, Susan Lindquist of MIT. Together, they inserted copies of the
> gene for the synaptic mark CPEB into yeast so that they could  
> experiment
> on them and see whether they were in fact prions. They found that
> indeed, CPEB can exist in two different states. In one, the protein
> roams the cell alone. In the other, it forces other CPEB to change  
> shape
> and form clumps with it. They also found that only when it takes on its
> prion form can CPEB bind to RNA.
>
> The researchers propose a simple but elegant hypothesis for how prions
> can build memories. They suggest that certain signals entering a  
> synapse
> can trigger CPEB to become a prion. As a prion, it can wake up sleeping
> RNA in the synapse, creating proteins for strengthening it. It also
> keeps grabbing other CPEB molecules and turning them into prions as
> well, so that even after the original prion has fallen apart, others
> continue to do the job. The neverending power of prions, in other  
> words,
> is what keeps our memories alive.
>
> In a commentary in the same issue of Cell, Robert Darnell of  
> Rockefeller
> University says that if this work holds up to scrutiny (if it's
> replicated in neurons rather than yeast, for one thing), it will prove
> "nothing less than extraordinary." It would be extraordinary enough if
> memory proved to be based on prions, but the finding--along with the
> earlier work on yeast--raises the possibility that prions actually do a
> lot of important things in our bodies, and that we cannot understand
> them unless we are willing to let go of our vision of life as nothing
> but genes creating proteins. That may not make this Christmas's roast
> any tastier, but it should help revive the low reputation of prions.
>
> --
>
> '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.
>
>
>
>
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