LAUSR

The protein misfolding mechanism of disease was first described almost 40 years ago in a group of neurodegenerative disorders caused by the prion protein (PrP) [1]. In these diseases, misfolding of cellular PrP (PrPC) into a β-sheet-rich conformation (PrPSc) results in PrPSc serving as a template for additional PrPC misfolding. Recent advances in cryoelectron microscopy (cryo-EM) have led to high-resolution structures for several misfolded protein aggregates isolated from brain tissue, including the PrPSc isolate 263K [2]. This model shows that the PrPSc proteins are stacked in register, with the R groups from each amino acid in the plane of the Ca backbone. The amides of the backbone are perpendicular to the plane, facilitating hydrogen bonds between protein layers to stabilize the flat, misfolded structure. In this conformation, PrPSc becomes a template for progressive misfolding of PrPC, with each replication event creating a new layer of intermolecular hydrogen bonds. Presumably, this mechanism leads to fibril formation and progressive neurodegeneration in a variety of distinct disorders, including Creutzfeldt–Jakob disease (CJD), fatal familial insomnia, and Gerstmann–Straussler–Scheinker disease. The prion hypothesis was initially viewed as incompatible with the observation that the disease agent (at the time thought to be a slow virus) was capable of inducing multiple disorders in the absence of a nucleic acid (discussed in [3]). This seeming conflict was resolved with the introduction of the strain hypothesis, which proposes that the disease a patient develops is determined by the distinct conformation PrPSc misfolds into, rather than mutations in a viral genome [4–6]. In this review cluster, the article by Dr. Jason Bartz discusses our current understanding of PrPSc strain biology in both human disease and other mammalian species, as well as the host and non-host factors that impact strain evolution in an individual [7]. Over the last 2 decades, research on other neurodegenerative diseases, including Alzheimer’s disease (AD) and multiple system atrophy (MSA), has increasingly shown that the protein misfolding mechanism is not exclusive to the conversion of PrPC into PrPSc [8, 9]. Consistent with the growing experimental observations that proteins like β-amyloid (Aβ), tau, and α-synuclein behave like prions, cryo-EM structures of recombinant fibrils or patient-derived protein aggregates containing these proteins all show in register templates, implying that the same mechanism that supports PrPSc propagation also enables self-templating of pathogenic Aβ, tau, and α-synuclein (several of these structures are discussed in [10–12]). Along with the growing need to expand the use of the term ‘prion’ to apply to a larger group of proteins is the need to define and investigate the disease-causing strains that result from their misfolding. Four reviews in this cluster focus on the phenotypic heterogeneity that manifests as a result of variability across non-PrPSc prion strains. Lau et al. discuss the structural and biological data supporting the hypothesis that distinct Aβ strains give rise to specific spatiotemporal patterns and types of pathology in AD patients, which likely impacts the clinical presentation of disease [10]. A similar diversity among amyotrophic lateral sclerosis (ALS) patients is now thought to arise from strain differences across proteins associated with the disorder. Ayers and Borchelt review the literature supporting the role of distinct SOD1, TDP-43, FUS, and C9orf72 strains in sub-types of familial ALS [13]. Tauopathies are a large and diverse group of disorders, each associated with a particular type and distribution of tau inclusions in the brain. Like PrPSc, where each prion disease is caused by its own unique strain, structural studies report conserved tau fibril conformations across patients with particular disorders, as discussed by Vaquer-Alicea et al. [11]. For example, the same conformation of misfolded tau has been resolved from both familial and sporadic AD patients [14], but this * Amanda L. Woerman [email protected]