Pathogenic prion structures at high resolution

Abstract

Numerous proteins are known to form ordered, self-propagating aggregates as underlying causes of neurodegeneration in proteinopathies such as Alzheimer's, Parkinson's, and prion diseases [1,2]. The prion-like properties of such aggregates can promote spreading within and, sometimes, between hosts as pathogens. Prions are protein-based transmissible agents that, unlike other types of pathogens, do not carry a specific nucleic acid genome. Classical prions are formed from the hosts' native prion protein (PrPC) and have long been known to be highly transmissible in many mammalian species (reviewed in [2,3]). Other more common proteinopathies have also been shown to be transmissible from humans to experimental, and usually transgenic "humanized,"animals, but the extent to which any such transmission occurs between humans remains under investigation and debate [4]. Extensive comparisons of brainderived versus synthetic PrP aggregates with in vitro self-propagating (seeding) activities have shown that conformational differences can profoundly affect their in vivo transmissibilities and pathogenicities, or lack thereof (e.g., [2,5]). For example, whereas approximately 10-15 g of brain-derived prions can be lethal, inoculation of a >109-fold larger amount of synthetic recombinant PrP fibrils can be innocuous [2]. Thus, in evaluating and understanding the risks posed by various self-replicative protein assemblies, it is crucial to consider conformational details. Fortunately, although the structures of prions and other proteopathic aggregates eluded high-resolution determination for decades, recent applications of cryogenic electron microscopy (cryo-EM) have begun to reveal these structures (e.g., [6-11]). Within the last year and a half, the first 3 near-atomic resolution cryo-EM structures of highly pathogenic brainderived prions have been reported [6-10]. Here, we highlight how these new prion structures have begun to address fundamental, long-standing questions in prion biology.