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Prions, prionoids and protein misfolding disorders

Abstract

Prion diseases are progressive, incurable and fatal neurodegenerative conditions. The term ‘prion’ was first nominated to express the revolutionary concept that a protein could be infectious. We now know that prions consist of PrPSc, the pathological aggregated form of the cellular prion protein PrPC. Over the years, the term has been semantically broadened to describe aggregates irrespective of their infectivity, and the prion concept is now being applied, perhaps overenthusiastically, to all neurodegenerative diseases that involve protein aggregation. Indeed, recent studies suggest that prion diseases (PrDs) and protein misfolding disorders (PMDs) share some common disease mechanisms, which could have implications for potential treatments. Nevertheless, the transmissibility of bona fide prions is unique, and PrDs should be considered as distinct from other PMDs.

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Fig. 1: The nucleation and fragmentation cycle of prions and prionoids.
Fig. 2: Structure of the prion protein and amino acid substitutions that have been linked to genetic prion diseases.
Fig. 3: Therapeutic approaches targeting protein aggregation.

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Acknowledgements

C.S. is the recipient of a Marie Curie Individual Fellowship. A.A. is the recipient of an advanced grant of the European Research Council and grants from the Swiss National Research Foundation, the Clinical Research Priority Programs ‘Small RNAs’ and ‘Human Haemato-Lymphatic Diseases’ of the University of Zurich and SystemsX.ch. Molecular graphics and analyses were performed with the University of California, San Francisco (UCSF) Chimaera package. Chimaera is developed by the Resource for Biocomputing, Visualization and Informatics at UCSF (supported by NIGMS P41-GM103311).

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Nature Reviews Genetics thanks E. Biasini, C. Soto and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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Correspondence to Adriano Aguzzi.

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Adriano Aguzzi is a founder and director of Mabylon Inc., a company devoted to the development of human antibodies for treating intractable diseases, including neurodegeneration. The authors are not aware of any other affiliations, memberships, funding or financial holdings that might be perceived as affecting the objectivity of this Review.

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Glossary

Prion diseases

(PrDs). A group of diseases caused by an infectious protein, which includes genetic, acquired and sporadic forms. PrDs have an overall incidence of one to two cases per million individuals per year.

Prion

The agent causing transmissible spongiform encephalopathies. As originally defined, the term does not have structural implications other than that a protein is an essential component. Although it is now generally accepted that the prion consists largely of the pathological aggregate of the prion protein, PrPSc, prions are defined as a biological activity rather than a physical entity. Hence, they can be measured by activity assays rather than by quantitating PrPSc.

Aggregates

In the context of this Review, the term ‘aggregate’ is used to denote the coalescence of misfolded proteins into highly ordered structures, typically resulting in the formation of fibrils.

Protein misfolding disorders

(PMDs). Disorders that are characterized by protein aggregates, which induce neurodegeneration if present in the brain.

Propagon

The minimal propagating unit of a misfolded protein, defined by its capacity to self-replicate in vitro and/or in vivo. A propagon that can transmit from a host individual to another individual is called a prion.

Prionoids

Protein aggregates that can propagate and spread between cells but for which transmissibility between individuals has not yet been demonstrated.

Polymorphisms

Any sites in the DNA sequence that are present in the general population in more than one state.

Penetrance

The percentage of individuals with a mutation who exhibit clinical symptoms. Most PRNP mutations are highly penetrant, meaning that most individuals with PRNP mutations develop prion disease.

Prion strains

Entities associated with distinct biochemical and neuropathological profiles, translating into a spectrum of incubation periods and clinical signs. Crucially, strain-specific traits are stable across serial transmission between isogenic hosts, indicating that they are encoded by the prion itself. Distinct structural assemblies of chemically identical pathological aggregates of the prion protein, PrPSc, are thought to underlie strain-ness.

Phase demixing

Process of membrane-less compartmentalization. Spontaneous demixing of two coexisting phases is driven by intermolecular interactions, a propensity that seems to be particularly high for proteins with low-complexity domains.

Excitotoxicity

Neuronal overstimulation caused by increased levels of the excitatory neurotransmitter glutamate leading to calcium overload and mitochondrial dysfunction and ultimately to neuronal cell death and memory loss.

Parabiosis

Surgical technique to anatomically connect two individuals. The shared circulatory system between the individuals allows specific factors to be assessed for their involvement in regulating physiological functions, behaviour and disease pathogenesis.

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Scheckel, C., Aguzzi, A. Prions, prionoids and protein misfolding disorders. Nat Rev Genet 19, 405–418 (2018). https://doi.org/10.1038/s41576-018-0011-4

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