Researchers Reverse Parkinson's in Animals
IRA FLATOW, host:
This is TALK OF THE NATION: SCIENCE FRIDAY. I'm Ira Flatow.
A couple of very hopeful stories related to nerve damage and disease this week. First one, a lesson - really offers us a lesson in basic research for all you naysayers who can't understand how working with lowly plants and animals can teach us anything about the human condition.
Label this one how learning what goes on inside that lowly yeast cell may yield an answer to treating Parkinson's Disease, because in research published this week in the journal Science, scientists have shown that once they found a way to reverse the damage done by proteins to yeast, they were able to apply that knowledge to reversing the damage done to nerves of rats suffering from Parkinson's Disease.
Here to talk about the seemingly strange connection is molecular biologist Susan Lindquist. Doctor Lindquist is a member of the Whitehead Institute for Biomedical Research where she's also an investigator for the Howard Hughes Medical Institute and professor of biology at MIT. Welcome to the program.
Dr. SUSAN LINDQUIST (Whitehead Institute for Biomedical Research; Investigator, Howard Hughes Medical Institute; Professor of Biology, MIT): Thank you. Glad to be here.
FLATOW: Can you walk us through this a little bit, how you get from a yeast to a rat?
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Dr. LINDQUIST: Sure. It does sound kind of strange, I will admit.
Dr. LINDQUIST: The - it's been appreciated recently that many really dreadful human diseases are due to proteins not taking their right shapes, to them folding into the wrong kind of a shape and then doing something bad. But these are really complicated, difficult diseases to study, and it's a difficult process to study.
And I've been working on protein folding for a good many years now, and we've worked on lots of different organisms. And it turns out that the fungus, the yeast Saccharomyces cerevisiae, which is well known to you because it's the organism that produces the leavened bread and beer and wine...
FLATOW: A common yeast.
Dr. LINDQUIST: Yep, a common yeast. It's a wonderful workhorse in the laboratory, and so what - the basic idea is the following. The code of life, DNA or the double helix, is linear, and the - but what that linear code does, primarily, is to code for the proteins that make up our bodies, and they're just thousands and thousands of these proteins and each one of them has a different sequence of amino acids and folds up into a way that does something different.
But it's the protein when it's first translated from that linear genetic code is also, originally, linear. It's just a long string of amino acids. And that protein does absolutely nothing until it folds up into a very, very specific shape, sort of like taking a sheet of origami paper and folding it into a dove or a sailboat or whatever.
Anyway, this problem in folding is an extremely difficult one for all living systems to cope with, because these proteins have to arrive at these folds at an incredibly crowded environment. There's just - it's really packed inside living cells; it's just things constantly bumping into each other and into, especially, with newly made proteins that are very, very sticky and have a (unintelligible) what we call go off-pathway in this fold.
So this problem is as ancient as life itself, because, of course, it's an aspect of decoding the genome and turning it into something useful, a useful protein. And living cells are always very, very crowded, because you get tremendous efficiencies out of having things so crowded. You can pass an electron from one protein to another. But it - they get this efficiency at a cost, and that is, it's hard for proteins to fold in there.
So that's an ancient problem, and it's universal. It's as old as life itself, and so that's a problem you can actually study very well in a yeast cell. And, let me tell you, yeast cells are a lot easier and cheaper and faster to work with than working with rats or other experimental lab animals.
So we - over the past several years, it's become clear that there's a particular protein called alpha-synuclein that mucks things up in the neurons and can lead to Parkinson's Disease. And so we decided, well, what we do know how to study in yeast cells is problems in protein folding, so let's take this protein, which is not folding properly in neurons, and have yeast cells express the protein and see what happens. And, sure enough, what we found was that the yeast cells died when this protein was folded.
What was really quite encouraging was the fact that we found that the yeast cells were just fine if they only had one copy of the gene for this protein that we're making a small amount of it. But if we just simply doubled the amount of the protein that they made, they suddenly died.
That was especially intriguing in light of Parkinson's Disease, because there are quite a few families that have early onset Parkinson's disease. Normally, this is a sporadic disease of the elderly, but there are some families in which the disease appears early, and it turns out that in many cases, it's - the cause has been discovered to be the fact that these people have extra copies of this alpha-synuclein gene. So there's extremely strong dosage sensitivity in people, as well as in yeast.
So that and several other aspects of the way the protein was behaving in yeast made us think that, well, maybe the cells were dying for a reason that had something to do with the reason why the neurons were dying in the human brain. So that gave us a really terrific position to start from, because in yeast, we could - there are - methods have been developed, quite literally, to simply allow you to ask the cell what's making it sick. And the way you do that is to take a library of yeast genes.
So thanks to collaborators at the Harvard Proteomics Facility, who've been busy creating some of the tools we've used, we can actually go into our freezers and get out dishes with 96 wells each, and we've got lots and lots of stacks of these dishes, and in each well, we have one individual gene for one particular yeast protein.
And so we could take, individually, all these genes and put them one by one into our yeast cells that were dying from this misfolded and misbehaving alpha-synuclein protein and ask, well, which of these genes made the cells better? And most of the genes had no effect at all. Some of the genes made them a little bit worse. But there was several different groups of genes that actually rescued the cells from this alpha-synuclein induced death.
And there's several that we still need to study. We don't know too much about them yet, although we're very excited about them. But one particular group was very intriguing, because they all - all of these genes had already been shown by other geneticists and cell biologists to function at a very particular place in the cell and doing a very particular thing, and that is controlling the trafficking of proteins around the cell.
So yeast cells, and our cells too, regulate trafficking of certain types of proteins by putting them inside membranes and little vesicle compartments. And they move proteins from one region of the cell to another region of the cell to another region of the cell. Then sometimes, they then move them out of the cell or sometimes they bring them into the cell.
But they do a lot of this through these membrane-bounded compartments. And what we found was that genes that helped the traffic at a particular stoplight point. This traffic, by the way, of these things going around the cell is actually controlled very, very carefully in the way that you can analogize what the traffic in the city of Boston being controlled by stoplights.
Dr. LINDQUIST: So we found that there was a pile-up basically happening at one particular corner. And we found that the genes that were rescuing these yeast cells were genes that pushed the traffic through. It's sort of like if you have a broken stoplight and you get a policeman out there and he says - he tells you to go on through.
And so we thought we - well, this is really intriguing, because this is a process that's common to all cells. We wondered, though, whether it could possibly be having anything to do with Parkinson's Disease. And, of course, the only way to look at that is to look in (unintelligible) systems.
And we were very fortunate to - and I would have to say that probably one of the best aspects of this study for me has been just the wonderful group of collaboratives who've been working with on this. It's really been a very, very much of a group effort.
So we worked with laboratories that were working on nematodes, which is a lowly little, very, very tiny worm. We worked with collaborators who were working on fruit flies. And with collaborators who were working on rat embryonic cells in culture. And my post-doc, who had been very much involved in helping define some of these genes in yeast - his name's Aaron Gitler - he actually took the relative of this yeast gene - which, as I told you, the process is very highly conserved, so it's not surprising that the proteins are very highly conserved.
So he took the mammalian version of that gene and he cloned it into systems that would allow them to be expressed in the worm - this is with Guy Caldwell's laboratory - or in the fruit fly - this is with Nancy Bonini's laboratory - or in red embryonic cultures and that was with Chris Rochet's laboratory.
And they had all, independently, previously built their own Parkinson's Disease model in these simple organisms. And, of course, those organisms are different from yeast cells in that they have real neurons. In fact, they not only have neurons, they have a particular kind of neuron called a dopaminergic neuron.
And the thing that's interesting about Parkinson's Disease, and many other nerve-degenerative diseases, is that they seem to hit particular neurons, they seem to be very specific. And so for that reason, in fact, most people had thought that the only way you could ever really study these diseases processes was actually to look at those particular neurons.
Our reasoning was that, well, maybe, something very general is going wrong and it's actually effecting all cells, it' just that particular neurons might be more vulnerable to that particular thing going wrong.
So our collaborators took these genes - in one particular gene that's really the major stoplight control center at this particular point of (unintelligible) trafficking - and they had made nematodes, for example, that were expressing alpha-synuclein, this bad protein for Parkinson's Disease, in the dopaminergic neurons of this little worm.
And, sure enough, when those worms were also expressing the protein that we'd identified in yeast, they got a lot better. Then we went to the fruit fly. And Nancy Bonini's group had made a fruit fly model where, again, they were over-expressing this alpha-synuclein. They found that it specifically killed these dopaminergic neurons. And then, when they expressed broadly this particular protein that we had found, it rescued the fruit flies.
And then, finally, in probably the best and most convincing case was the work with Chris Rochet's laboratory and that was with real mammalian neurons. So he takes the midbrains out of embryonic rats and puts them into a culture dish.
FLATOW: I'm going to have to stop...
Dr. LINDQUIST: And then he...
FLATOW: Dr. Lindquist, we're getting to the punch line.
Dr. LINDQUIST: Yeah.
FLATOW: You're such a great storyteller. I don't want to interrupt you.
Dr. LINDQUIST: Sure.
FLATOW: But we have to take a break. You've gone on for ten minutes. I think you've told the longest story ever on SCIENCE FRIDAY. So stay with us - and it was great. We'll be right back after this short break with Dr. Lindquist. Stay with us, we'll be right back.
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FLATOW: I'm Ira Flatow. This is TALK OF THE NATION: SCIENCE FRIDAY, from NPR News.
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FLATOW: You're listening to TALK OF THE NATION: SCIENCE FRIDAY. I'm Ira Flatow. We're talking with Dr. Susan Lindquist of the Whitehead Institute, telling us -getting directly into this great story about the connection between yeast and these laboratory rats who now express the same gene. Tell us what happened there.
Dr. LINDQUIST: So it wasn't actually whole rats. It - the experiments with whole rats take a long time and they're difficult and expensive. So what we've been able to do work with actually is rat embryonic neurons in a culture dish. And, of course, eventually, we would like to go into the whole animals. But what we've done already is, I think, pretty promising.
So we had identified this gene from yeast that looked like it was taking cells that were expressing this bad protein in Parkinson's Disease, this alpha-synuclein protein, and fixing the yeast cells. And we took the related gene from mammals. And worked with Chris Rochet, who'd set up a embryonic rat culture model for Parkinson's Disease by - he'd take out the midbrain region of these rats and put them in culture. And, of course, it'd contain a mixture of all different kinds of neurons. But he then applied an insult that's associated with Parkinson's Disease, specifically, in fact, a mutant form of this alpha-synuclein protein. And what it does is it specifically causes these dopaminergic neurons, the ones that get sick in Parkinson's Disease, to die in its culture dish.
And what we found is that when we expressed this fixit protein from yeast, at the same time as the rat cells were being exposed to the alpha-synuclein protein, they survived. So taking, you know, a disease, which is thought to have been very, very specific to a very particular group of neurons, what we really showed there was that what's happening is something very, very basic is going wrong.
It's a very, very basic cell process that all cells have. And it's just that the dopaminergic neurons are particularly sensitive. When that goes wrong a little bit, people will wind up getting problems in their 60s or 70s. If you were to just wait another 100 years or so, probably you'd see a lot of their other cells having problems, too. But it's the dopaminergic neurons that are killed first.
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