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How Prions Promote Change

Susan Lindquist
Image: University of Chicago Medical Center

Evolutionary change presents a number of enigmas. In particular, scientists have long puzzled over how traits that require several independent genetic changes can emerge so suddenly. Those individual changes are likely to be disadvantageous to the organism, so natural selection ought to weed them out. But a report published today in the journal Nature offers a tantalizing clue: the key may lie with the misshapen proteins implicated in such incurable neurodegenerative illnesses as Mad Cow disease and its human counterpart, Creutzfeldt-Jakob disease.

Researchers at the University of Chicago examined prions in yeast cells. These prions fold incorrectly in the same telltale way as do the mammalian variety, and the mutations are likewise passed down from generation to generation. But yeast prions do not harm their hosts. According to the study's results, what they may do is enhance the yeast's ability to adapt to rapidly changing environments.

The team focused on a protein known as Sup35. When functioning properly, Sup35 tells the protein-production machinery within a cell when to stop. In its prion state, though, Sup35 doesn't do its job; instead it just prompts other prion proteins to misfold. Without the direction of Sup35, the cell machinery keeps running, and, as a result, previously hidden regions of the organism's genome are suddenly expressed. Under normal circumstances, mutations can build up in these regions, hidden from natural selection. Prion activity unveils all at once those mutations that have been accumulating for some time.

Thus, with a flick of this prion "switch" the cell changes its diet, for instance, or its resistance to antibiotics. "It's an all-or-nothing switch, with the changes immediately inherited by all the progeny," explains lead author Susan Lindquist (above). "But because the cell maintains the ability to switch back, the prion switch allows cells to occupy a new niche without losing their capacity to occupy the old."

The researchers speculate that a shape change in an inconsequential part of Sup 35 may have brought about the prion switch by accident. But the fact that it has persisted suggests that it confers some sort of evolutionary advantage. "It may be that the prion switch offers yeast a way to respond to commonly fluctuating environments," Lindquist proposes. "During its evolution S. cerevisiae (brewer's yeast) must have met with such erratic environments that it needed to maintain a global mechanism for exploiting genome-wide variation." And the prion switch may well be operating in other organisms, driving rates and mechanisms of evolutionary change. "We need to expand our understanding of inheritance," she remarks. "It involves much more than a certain nucleic acid sequence of DNA."

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