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Qnas with Susan L. Lindquist QnAs QnAs with Susan L. Lindquist rions defy molecular biology’s cen- insert their protein into yeast cells; and it tral dogma. Misfolded proteins did undergo a prion-like conformational that self-perpetuate, prions were switch, rendering the protein active. What Pfi rst isolated in the early 1980s as we think is happening—and the evidence is the cause of a fatal sheep disease called getting stronger—is that the protein enters scrapie. Since then, prions have been im- a prion state in nerve cells at certain kinds plicated in human neurodegenerative of synapses and helps make proteins that diseases, composing a rogue’s gallery of are involved in building the synapses. That deadly disease agents. Susan Lindquist, might produce a form of molecular sub- a member of the National Academy of strate for local memory in the synapse. Sciences and a professor of biology at the Further, we have found that when the switch Massachusetts Institute of Technology’s Susan L. Lindquist. to the prion state occurs, it can result in a Whitehead Institute for Biomedical Re- handful of self-perpetuating prion states of search, has found that prions may have varying levels of activity that persist for a little-appreciated positive side. Lindquist that first prion we looked at, the normal years. So, the thinking goes, this might be a casts these seeming biochemical misfits form of the protein—called the transla- mechanism for maintaining synapses of dif- in a surprising evolutionary role: Her tion termination factor—helps ribosomes ferent strengths. studies have revealed that prions might [cells’ protein synthesizing machinery] rec- PNAS: Was there skepticism regarding such help cells adapt to a host of environmental ognize stop codons and terminate transla- positive roles for prions, which are largely pressures. Lindquist explains this still- tion. When that protein switches to its seen as destructive proteins that cause contentious idea to PNAS readers. prion form, it is sequestered in an aggre- gate. As a result, the ribosomes continue devastating diseases? PNAS: How did you suspect that prions translation. That can change the abun- Lindquist: It is still a fairly controversial might have a positive role in cells? dance of the protein or produce new pro- idea. Some people believe it, and others Lindquist: We were working on a heat shock teins that might confer adaptive traits. don’t. That said, we’ve found many new — — protein Hsp104 involved in a form of PNAS: So the prion functions as a switch prions that seem to suggest that prion stress tolerance in yeast when I got a call that can sometimes benefit the organism? switching is a fairly common mechanism to from Yury Chernoff. He was studying a acquire new traitsat least in yeast cells. mysterious genetic factor that affected the Lindquist: Yes, we now know there are lots fl PNAS: What are the evolutionary im- organism’s fidelity of protein translation. of these prions; and ipping on the switch fi to a prion state can turn the function of plications of these bene cial roles played He had found that Hsp104 affected the by prions? inheritance of this factor. We had reported the protein on or off and potentially pro- that Hsp104 allows cells to tolerate stress, vide yeast cells with novel, heritable traits. Lindquist: One of the great conundrums in ’ but we hadn t reported how. We knew that PNAS: Now the million-dollar question: What evolution is how complexity is achieved Hsp104 takes protein aggregates apart; triggers the switch? and inherited. For an organism to evolve but we hadn’t been able to get it published novel traits, several spontaneous changes because no one would believe us—it was, Lindquist: That may be the best part. Prions must occur together, and prions illustrate after all, very unexpected. So we started are fundamentally a protein folding prob- how that might happen in nature all at working with Yury on how a protein fold- lem. Every once in a while, cells might once. We’ve found that about 25% of the ing agent affected the inheritance of this switch some of their proteins into and out time when a protein switches to a prion factor. A few months later Reed Wickner of the prion state, just out of happenstance. state, it allows the organism to acquire bene- published the idea that the mysterious We call this a “bet-hedging” strategy; but ficial traits. We believe it is fairly widespread factor was possibly a prion. We showed stress and unfavorable environments cause in biology. protein folding problems and increase the through biochemical studies that this in- PNAS: Can studying the beneficial proper- frequency of that switch. It’s an illustration herited prion self-perpetuated as an ag- ties of prions help address protein aggre- of environmental change altering the pace gregate. In distantly related organisms the gation diseases like Parkinson’s disease and of evolution. It’s very Lamarckian: Heritable gene for the prion is highly conserved, in- Alzheimer’sdisease? cluding the sequence of the protein do- traits arise as adaptations before they are main that we believed was serving as the hardwired into the genome. Lindquist: There is growing evidence to suggest that it may not be the amyloids aggregation template. The degree of evo- PNAS: In collaboration with neuroscientist themselves that are toxic to cells (they are lutionary conservation of this protein Eric Kandel you found that prions might highly stable, inert aggregates) but that it’s made us wonder whether the prion played influence learning and memory. Can you the pre-amyloids that wreak havoc in those a physiologically important role in yeast. explain how? PNAS: diseases. Amyloids begin as a sort of olig- What did your studies reveal? Lindquist: Eric Kandel was studying proteins omeric pre-amyloid state, which we be- Lindquist: Indeed, the prion affected the locatedinsynapsesthathelpmaintainthem lieve many prions are capable of adopting. ability of yeast to grow under many differ- in an active, stable state—a biochemical By studying prions we’re learning that to ent conditions. Yeast cells, which grow in basis for learning and memory. Kausik Si, prevent protein aggregation diseases, we diverse, changing environments, can spon- a postdoc of Kandel’s, found that one of the might have to either prevent those pro- taneously gain or lose prions. Prions might proteins they were studying had a domain on teins from going into the oligomeric state help them rapidly adapt to those environ- it that looked like a yeast prion, suggesting or hasten the transformation of the oligo- ments, such as changes in salt, oxygen, and that the protein might assemble into an or- meric, pre-amyloid state into a stable am- carbon sources, by conferring new pheno- dered aggregate. So Kandel walked into my yloid state. types. The prions cause the yeast to read office one day, asking whether prions might their genetic information differently. With be involved in memory. We helped them Prashant Nair, Science Writer www.pnas.org/cgi/doi/10.1073/pnas.1118394108 PNAS Early Edition | 1of1 Downloaded by guest on September 26, 2021.
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