Abstract
Although it is not yet universally accepted that all neurodegenerative diseases (NDs) are prion disorders, there is little disagreement that Alzheimer’s disease (AD), Parkinson’s disease, frontotemporal dementia (FTD), and other NDs are a consequence of protein misfolding, aggregation, and spread. This widely accepted perspective arose from the prion hypothesis, which resulted from investigations on scrapie, a common transmissible disease of sheep and goats. The prion hypothesis argued that the causative infectious agent of scrapie was a novel proteinaceous pathogen devoid of functional nucleic acids and distinct from viruses, viroids, and bacteria. At the time, it seemed impossible that an infectious agent like the one causing scrapie could replicate and exist as diverse microbiological strains without nucleic acids. However, aggregates of a misfolded host-encoded protein, designated the prion protein (PrP), were shown to be the cause of scrapie as well as Creutzfeldt–Jakob disease (CJD) and Gerstmann–Sträussler–Scheinker syndrome (GSS), which are similar NDs in humans. This review discusses historical research on diseases caused by PrP misfolding, emphasizing principles of pathogenesis that were later found to be core features of other NDs. For example, the discovery that familial prion diseases can be caused by mutations in PrP was important for understanding prion replication and disease susceptibility not only for rare PrP diseases but also for far more common NDs involving other proteins. We compare diseases caused by misfolding and aggregation of APP-derived Aβ peptides, tau, and α-synuclein with PrP prion disorders and argue for the classification of NDs caused by misfolding of these proteins as prion diseases. Deciphering the molecular pathogenesis of NDs as prion-mediated has provided new approaches for finding therapies for these intractable, invariably fatal disorders and has revolutionized the field.
Highlights
Prions are composed of host-encoded proteins that adopt alternative conformations, which are self-propagating [1,2,3,4]
This study revealed the greater efficiency of homotypic interactions between PrPC and PrPSc for the replication of prions
neurodegenerative diseases (NDs) involve a fluid set of protein conformations that, at present, cannot be predicted from the amino acid sequence, which at least partially explains the lack of any effective therapies for prion diseases caused by prion protein (PrP), Aβ, tau, α-synuclein, and other neurodegenerative prion diseases
Summary
Prions are composed of host-encoded proteins that adopt alternative conformations, which are self-propagating [1,2,3,4]. Tauopathy from patients with AD was transmitted to human tau transgenic mice, arguing that tau prions can induce conformations in wild-type or mutant tau protein that initiate prion propagation [13]. Α-synuclein prions that cause multiple system atrophy (MSA) can transmit disease to transgenic mice and infect cultured reporter cells [14,15]. The transmission of pathology from diseases involving Aβ, tau, or α-synuclein misfolding in these (and other) NDs argues that the approaches used to unravel the mystery of scrapie, the prototypical PrP prion disease, can be successfully applied to understanding other NDs. The shared feature of transmissibility, along with other properties discussed below, suggest that prion diseases can involve proteins other than PrP, just as there are a variety of viral, bacterial, and rickettsial disorders
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