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Prions as adaptive conduits of memory and inheritance

Key Points

  • 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.

Abstract

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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Figure 1: The prion hypothesis and the yeast prion [PSI+]
Figure 2: [PSI+] reveals hidden genetic variation and can confer selective advantages.
Figure 3: Maintenance of long-term facilitation by the ApCPEB prion.

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Acknowledgements

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.

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Correspondence to James Shorter or Susan Lindquist.

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Related links

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DATABASES

Entrez Protein

anterior open

ApCPEB

brahma

CG5735-PA

CPEB3

Polycomb

polyhomeotic

PrP

TIA1

trithorax

trithorax-like

zeste

OMIM

Alzheimer disease

Creutzfeldt-Jakob disease

Gerstmann-Sträussler-Scheinker syndrome

Huntington disease

kuru

Parkinson disease

type II diabetes

Saccharomyces genome database

Gat1

Gln3

Hsp104

New1

Rnq1

Sis

Snf5

Sup35

Swi1

Ure2

FURTHER INFORMATION

Chronic Wasting Disease Alliance

FoldIndex©

Lindquist laboratory

UK Department for Environment Food and Rural Affairs Bovine Spongiform Encephalopathy website

Veterinary Services Scrapie Program

Glossary

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.

CONFORMER

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.

HETEROKARYON

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.

AMYLOID

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.

CHAOTROPE

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.

BIOFILM

A proliferation on an inert surface of aggregated microbial colonies that have increased resistance to antimicrobial therapies. Biofilms contribute to many human infections.

SPONGIOSIS

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.

ISOGENIC

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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