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Atomic structures suggest determinants of transmission barriers in mammalian prion disease.

ABSTRACT: Prion represents a unique class of pathogens devoid of nucleic acid. The deadly diseases transmitted by it between members of one species and, in certain instances, to members of other species present a public health concern. Transmissibility and the barriers to transmission between species have been suggested to arise from the degree to which a pathological protein conformation from an individual of one species can seed a pathological conformation in another species. However, this hypothesis has never been illustrated at an atomic level. Here we present three X-ray atomic structures of the same segment from human, mouse, and hamster PrP, which is critical for forming amyloid and confers species specificity in PrP seeding experiments. The structures reveal that different sequences encode different steric zippers and suggest that the degree of dissimilarity of these zipper structures gives rise to transmission barriers in prion disease, such as those that protect humans from acquiring bovine spongiform encephalopathy (BSE) and chronic wasting disease (CWD).

SUBMITTER: Apostol MI

PROVIDER: S-EPMC3068218 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Atomic structures suggest determinants of transmission barriers in mammalian prion disease.

Apostol Marcin I MI Wiltzius Jed J W JJ Sawaya Michael R MR Cascio Duilio D Eisenberg David D

Biochemistry 20110311 13

Prion represents a unique class of pathogens devoid of nucleic acid. The deadly diseases transmitted by it between members of one species and, in certain instances, to members of other species present a public health concern. Transmissibility and the barriers to transmission between species have been suggested to arise from the degree to which a pathological protein conformation from an individual of one species can seed a pathological conformation in another species. However, this hypothesis ha ...[more]

PMID: 21323366

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Project description:RepA is a bacterial protein that builds intracellular amyloid oligomers acting as inhibitory complexes of plasmid DNA replication. When carrying a mutation enhancing its amyloidogenesis (A31V), the N-terminal domain (WH1) generates cytosolic amyloid particles that are inheritable within a bacterial lineage. Such amyloids trigger in bacteria a lethal cascade reminiscent of mitochondrial impairment in human cells affected by neurodegeneration. To fulfill all the criteria to qualify as a prion-like protein, horizontal (intercellular) transmissibility remains to be demonstrated for RepA-WH1. Since this is experimentally intractable in bacteria, here we transiently expressed in a murine neuroblastoma cell line the soluble, barely cytotoxic RepA-WH1 wild type [RepA-WH1(WT)] and assayed its response to exposure to in vitro-assembled RepA-WH1(A31V) amyloid fibers. In parallel, murine cells releasing RepA-WH1(A31V) aggregates were cocultured with human neuroblastoma cells expressing RepA-WH1(WT). Both the assembled fibers and donor-derived RepA-WH1(A31V) aggregates induced, in the cytosol of recipient cells, the formation of cytotoxic amyloid particles. Mass spectrometry analyses of the proteomes of both types of injured cells pointed to alterations in mitochondria, protein quality triage, signaling, and intracellular traffic. Thus, a synthetic prion-like protein can be propagated to, and become cytotoxic to, cells of organisms placed at such distant branches of the tree of life as bacteria and mammalia, suggesting that mechanisms of protein aggregate spreading and toxicity follow default pathways.IMPORTANCE Proteotoxic amyloid seeds can be transmitted between mammalian cells, arguing that the intercellular exchange of prion-like protein aggregates can be a common phenomenon. RepA-WH1 is derived from a bacterial intracellular functional amyloid protein, engineered to become cytotoxic in Escherichia coli Here, we have studied if such bacterial aggregates can also be transmitted to, and become cytotoxic to, mammalian cells. We demonstrate that RepA-WH1 is capable of entering naive cells, thereby inducing the cytotoxic aggregation of a soluble RepA-WH1 variant expressed in the cytosol, following the same trend that had been described in bacteria. These findings highlight the universality of one of the central principles underlying prion biology: No matter the biological origin of a given prion-like protein, it can be transmitted to a phylogenetically unrelated recipient cell, provided that the latter expresses a soluble protein onto which the incoming protein can readily template its amyloid conformation.

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Atomic structures suggest determinants of transmission barriers in mammalian prion disease.

Publications

Atomic structures suggest determinants of transmission barriers in mammalian prion disease.

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