Prions are transmissible, self-replicating protein conformations that cause neurodegenerative diseases in mammals, but function as beneficial genetic elements in fungi.
The generation of synthetic prions provides definitive support for the prion hypothesis.
Beneficial fungal prions are regulated by protein-remodelling factors (such as Hsp104) and molecular chaperones (such as Hsp40).
The yeast prion [PSI+] confers evolvability and phenotypic plasticity, which impart selective advantages
Prions that mimic loss-of-function mutations might act as evolutionary capacitors.
Glutamine (Gln)/asparagine (Asn)-rich domains of yeast prions confer all aspects of prion behaviour, and are broadly distributed in many proteins of plants, fungi and metazoa, indicating that prions might be more common than previously thought.
CPEB prions might function in the formation of long-term memory.
Prions might also be involved in the construction of transcriptional memory and genome-wide expression patterns.
Changes in protein conformation drive most biological processes, but none have seized the imagination of scientists and the public alike as have the self-replicating conformations of prions. Prions transmit lethal neurodegenerative diseases by means of the food chain. However, self-replicating protein conformations can also constitute molecular memories that transmit genetic information. Here, we showcase definitive evidence for the prion hypothesis and discuss examples in which prion-encoded heritable information has been harnessed during evolution to confer selective advantages. We then describe situations in which prion-enciphered events might have essential roles in long-term memory formation, transcriptional memory and genome-wide expression patterns.
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We thank Kent Matlack, Jessica Brown, Todd Sangster, Jens Tyedmers, Walker Jackson, Martin Dünnwald, Sven Heinrich and Ram Krishnan for invaluable comments on the manuscript. J.S. was supported by a Charles A. King Trust post-doctoral fellowship. S.L. was supported by a National Institutes of Health grant.
The authors declare no competing financial interests.
Saccharomyces genome database
- PHENOTYPIC SPACE
A multi-dimensional continuum of all possible phenotypes.
- ADAPTIVE LANDSCAPE
A graph of the average fitness of a population in relation to the frequencies of genotypes in the population.
Any of two or more isomers that differ only in their three dimensional conformation.
- CODICAL DOMAIN
The domain of natural selection dealing solely with self-replicating information as opposed to material entities.
Any cell with more than one nucleus and where the nuclei are not all of the same genetic constitution, or a tissue composed of such cells.
A general term for protein aggregates that accumulate as fibres of 7–10nm in diameter with common structural features including: β-pleated sheet conformation, resistance to detergents and proteases, and the ability to bind such dyes as Congo red and Thioflavin T and S.
Any substance (usually ions) that increases the transfer of apolar groups to water by decreasing the 'ordered' structure of water. Chaotropes alter secondary, tertiary and quaternary protein structure.
A proliferation on an inert surface of aggregated microbial colonies that have increased resistance to antimicrobial therapies. Biofilms contribute to many human infections.
A form of neurodegeneration involving the formation of large fluid-filled spaces (vacuoles) in the brain, which if widespread, induces a sponge-like appearance of the brain. This spongiform change is a general (but not universal) pathological hallmark of prion diseases.
- PURIFYING SELECTION
A mode of natural selection that preserves the adapted condition, and is observed as a large excess of synonymous substitutions over non-synonymous substitutions in functionally important genes.
- CRYPTIC GENETIC VARIATION
Existing genetic variation that makes no contribution to the normal range of phenotypes, but which can modify phenotypes in response to environmental change or the introduction of novel genetic elements.
Describing two or more individuals that possess exactly the same genotype.
- VALLEY CROSSING
The process of moving from one adaptive peak to another on an adaptive landscape by crossing a valley. Valleys correspond to genotypic frequencies at which average fitness is low.
- ADAPTIVE PEAK
A region in an adaptive landscape corresponding to genotypic frequencies at which the average fitness is high.
- MEIOTIC DRIVE
Any process that causes some alleles to be over-represented in gametes formed during meiosis.
- EVOLUTIONARY CAPACITOR
An entity (for example, Hsp90) that buffers genotypic variation under neutral conditions, thereby allowing the accumulation of hidden polymorphisms.
- LONG-TERM FACILITATION
The long-lasting increase in synaptic activity that contributes to long-term memory and results from prolonged or iterated exposure of synapses to neurotransmitters, which induce the synthesis of new proteins leading to the stabilization of new synaptic connections.
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Shorter, J., Lindquist, S. Prions as adaptive conduits of memory and inheritance. Nat Rev Genet 6, 435–450 (2005). https://doi.org/10.1038/nrg1616
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