Priority study shows that the toxicity of antiprion antibodies is mediated by the flexible tail of the prion protein, provides key clues on prion toxicity mechanisms.

Prion infections cause lethal neurodegeneration, a process that requires the presence in target cells of cellular prion protein PrPC, which contains a globular domain hinged to a long amino-proximal flexible tail.


A study recently published by Priority researcher Adriano Aguzzi, his group, and collaborators (Tiziana Sonati et al. Nature, 2013, 501:102-6) describes rapid neurotoxicity in mice exposed to ligands targeting the α1 and α3 helices of the PrPC globular domain. Ligands included seven different monoclonal antibodies, monovalent Fab1 fragments and recombinant single-chain variable fragment miniantibodies. Similar to prion infections, the toxicity of these globular domain ligands requires the presence of PrPC and is associated with calpain activation and antagonized by calpain inhibitors. Neurodegeneration was accompanied by a burst of reactive oxygen species, and suppressed by antioxidants.

Furthermore, genetic ablation of the superoxide-producing enzyme NOX2 (also known as CYBB) protected mice from globular domain ligand toxicity. Strikingly, neurotoxicity was prevented by deletions of the octapeptide repeats within the flexible tail which did not appreciably compromise globular domain antibody binding.

All this strongly suggests that the flexible tail is required to transmit toxic signals that originate from the globular domain. In agreement with this view, various octapeptide ligands prevented the toxicity of globular domain ligands while not interfering with their binding. The authors of the study conclude that PrPC consists of two functionally distinct modules, with the globular domain and the flexible tail exerting regulatory and executive functions, respectively. Octapeptide ligands also prolonged the life of mice expressing the toxic PrPC mutant, PrP(Δ94-134), indicating that the flexible tail mediates toxicity in two distinct PrPC-related conditions.

Flexible tail-mediated toxicity may conceivably play a role in certain prion pathologies, such as familial Creutzfeldt-Jakob disease in humans bearing supernumerary octapeptides. Furthermore, these findings provide key clues on the mechanisms by which prions exert their toxic, lethal effects, which in turn might be used for the rational design of therapies.

(Adapted from Nature, 2013, 501:102-6)


Date published:


Figure 1: Epitope specificity of the neurotoxicity mediated by antiprion antibodies. (From: Tiziana Sonati et al., Journal name: Nature 501, 102–106, 2013). a, Antibody binding sites on PrP(23–230). POM6–9, 13, 15 and 17 bind helix α1 and compete with POM1 (ref. 3). POM6 and POM7 (light orange) show additional binding sites at helix α2 (dark orange), whereas POM5 recognizes a unique epitope at the β2–α2 transition (green). The GD image was rendered using the PDB structure 2L1H. b, NeuN morphometry of tga20 COCS treated with various antibodies to FT and GD epitopes (same colour codes as in panel a). Treatment modalities: 67 nM, 10 days (†); 200 nM, 21 days (‡); 333 nM, 14 days (§); or 67 nM, 21 days (unlabelled columns). CGC loss was induced by antibodies to helices α1 (light violet, orange, red) and α3 (blue). Antibodies binding the CC2 (magenta) were toxic only at higher concentrations and after protracted incubation. Antibodies against the OR (turquoise) were consistently innocuous. Graph shows percentage of NeuN+ pixels within the CGC layer, normalized against treatment with a random pool of IgG antibodies. One-way ANOVA with Dunnett’s post-hoc test, ***P < 0.001, **P < 0.01, error bars represent mean ± s.d., n = 9 biological replicates. NS, not significant.


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