Contents lists available at ScienceDirect Seminars in Cell & Developmental Biology journal homepage: www.elsevier.com/locate/semcdb Prions and Prion-like assemblies in neurodegeneration and immunity: The emergence of universal mechanisms across health and disease Ailis O’Carroll, Joanne Coyle, Yann Gambin* EMBL Australia Node in Single Molecule Sciences, and School of Medical Sciences, Faculty of Edicine, The University of New South Wales, Sydney, Australia ARTICLE INFO Keywords: Prions Prion-like SCAF Amyloid Polymerization Innate immunity Neurodegeneration ABSTRACT Prion-like behaviour is an abrupt process, an “all-or-nothing” transition between a monomeric species and an “infinite” fibrillated form. Once a nucleation point is formed, the process is unstoppable as fibrils self-propagate by recruiting and converting all monomers into the amyloid fold. After the “mad cow” episode, prion diseases have made the headlines, but more and more prion-like behaviours have emerged in neurodegenerative diseases, where formation of fibrils and large conglomerates of proteins deeply disrupt the cell homeostasis. More in- terestingly, in the last decade, examples emerged to suggest that prion-like conversion can be used as a positive gain of function, for memory storage or structural scaffolding. More recent experiments show that we are only seeing the tip of the iceberg and that, for example, prion-like amplification is found in many pathways of the immune response. In innate immunity, receptors on the cellular surface or within the cells ‘sense’ danger and propagate this information as signal, through protein-protein interactions (PPIs) between ‘receptor’, ‘adaptor’ and ‘effector’ proteins. In innate immunity, the smallest signal of a foreign element or pathogen needs to trigger a macroscopic signal output, and it was found that adaptor polymerize to create an extreme signal amplification. Interestingly, our body uses multiple structural motifs to create large signalling platform; a few innate proteins use amyloid scaffolds but most of the polymers discovered are composed by self-assembly in helical filaments. Some of these helical assemblies even have intercellular “contamination” in a “true” prion action, as demon- strated for ASC specks and MyD88 filaments. Here, we will describe the current knowledge in neurodegenerative diseases and innate immunity and show how these two very different fields can cross-seed discoveries. 1. From prions to prion-likes assemblies in neurodegeneration 1.1. Discovery of prions, proteins with a bad reputation The term “prion diseases” specifically refers to Transmissible spongiform encephalopathies (TSEs), a group of incurable neurode- generative disorders that can affect humans and animals. TSEs are predominant in cattle, sheep, goats and cervid species and were ob- served as early as the 18th century in sheep (referred to as scrapie disease) [1]. The first human case of TSE was described in 1921 by A. Jakob [2] but it was the thrilling discovery of Kuru in Papua New Guinea that suggested that this scrapie-like disease could be transmitted between humans [3]. C. Gajdusek received the Nobel Prize in 1976 for elucidating this “new mechanism for the origin and dissemination of infectious diseases”. It is likely that the transmission of Kuru was not linked to cannibalism, but instead to the ritual of massaging the scalps of children with the brains of the deceased in the Fore tribe; never- theless, it brought TSEs into the domain of human infectious diseases. The discovery of DNA and nucleic acids provided a powerful explana- tion for the mechanisms of transmission of infectious agents such as viruses, but it became clear that these were not the infectious agents driving the development of TSEs. The hypothesis that scrapie was transmitted by proteins only was first advanced by Alper and Griffith [4]; the work led by S. Prusiner proved that the “proteinaceous in- fectious particles” (or prions) found in brain homogenates could resist all treatments that would denature nucleic acids and so the infectious agent did not utilise genetic components. The prion hypothesis earned S. Prusiner a Nobel prize; it asserted a new paradigm of information storage and transfer in biological systems, as genetic instructions are not transmitted with the prion to the uninfected organisms but encoded into the structure of the protein PrP itself. As we will describe later in this review, the pathological misfolding of the prion protein and formation of highly ordered protein aggregates confers extraordinary properties of self-propagation and explains the multiple hallmarks of infectious diseases caused by specific strains, their transmissibility and the selected barriers that occur between https://doi.org/10.1016/j.semcdb.2019.11.012 Received 12 November 2019; Accepted 22 November 2019 ⁎ Corresponding author. E-mail address: y.gambin@unsw.edu.au (Y. Gambin). Seminars in Cell and Developmental Biology xxx (xxxx) xxx–xxx 1084-9521/ Crown Copyright © 2019 Published by Elsevier Ltd. All rights reserved. Please cite this article as: Ailis O’Carroll, Joanne Coyle and Yann Gambin, Seminars in Cell and Developmental Biology, https://doi.org/10.1016/j.semcdb.2019.11.012