Publication Date:
2013-08-02
Description:
Prion infections cause lethal neurodegeneration. This process requires the cellular prion protein (PrP(C); ref. 1), which contains a globular domain hinged to a long amino-proximal flexible tail. Here we describe rapid neurotoxicity in mice and cerebellar organotypic cultured slices exposed to ligands targeting the alpha1 and alpha3 helices of the PrP(C) globular domain. Ligands included seven distinct monoclonal antibodies, monovalent Fab1 fragments and recombinant single-chain variable fragment miniantibodies. Similar to prion infections, the toxicity of globular domain ligands required neuronal PrP(C), was exacerbated by PrP(C) overexpression, was associated with calpain activation and was antagonized by calpain inhibitors. Neurodegeneration was accompanied by a burst of reactive oxygen species, and was suppressed by antioxidants. Furthermore, genetic ablation of the superoxide-producing enzyme NOX2 (also known as CYBB) protected mice from globular domain ligand toxicity. We also found that neurotoxicity was prevented by deletions of the octapeptide repeats within the flexible tail. These deletions did not appreciably compromise globular domain antibody binding, suggesting that the flexible tail is required to transmit toxic signals that originate from the globular domain and trigger oxidative stress and calpain activation. Supporting this view, various octapeptide ligands were not only innocuous to both cerebellar organotypic cultured slices and mice, but also prevented the toxicity of globular domain ligands while not interfering with their binding. We conclude that PrP(C) 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 PrP(C) mutant, PrP(Delta94-134), indicating that the flexible tail mediates toxicity in two distinct PrP(C)-related conditions. Flexible tail-mediated toxicity may conceivably play a role in further prion pathologies, such as familial Creutzfeldt-Jakob disease in humans bearing supernumerary octapeptides.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sonati, Tiziana -- Reimann, Regina R -- Falsig, Jeppe -- Baral, Pravas Kumar -- O'Connor, Tracy -- Hornemann, Simone -- Yaganoglu, Sine -- Li, Bei -- Herrmann, Uli S -- Wieland, Barbara -- Swayampakula, Mridula -- Rahman, Muhammad Hafizur -- Das, Dipankar -- Kav, Nat -- Riek, Roland -- Liberski, Pawel P -- James, Michael N G -- Aguzzi, Adriano -- England -- Nature. 2013 Sep 5;501(7465):102-6. doi: 10.1038/nature12402. Epub 2013 Jul 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Neuropathology, University Hospital Zurich, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23903654" target="_blank"〉PubMed〈/a〉
Keywords:
Amino Acid Sequence
;
Animals
;
Antibodies/*immunology/*toxicity
;
Antibodies, Monoclonal/immunology/toxicity
;
Binding Sites, Antibody
;
Calpain/metabolism
;
Cerebellum
;
Creutzfeldt-Jakob Syndrome/metabolism
;
Cross-Linking Reagents
;
Epitope Mapping
;
Female
;
Immunoglobulin Fab Fragments/immunology/toxicity
;
In Vitro Techniques
;
Ligands
;
Male
;
Membrane Glycoproteins/metabolism
;
Mice
;
Molecular Sequence Data
;
NADPH Oxidase/metabolism
;
Neurodegenerative Diseases/metabolism
;
Oxidative Stress
;
*Pliability
;
PrPC Proteins/chemistry/genetics/immunology
;
Prions/*chemistry/genetics/*immunology
;
Reactive Oxygen Species/metabolism
;
Sequence Deletion/genetics
;
Single-Chain Antibodies/immunology/toxicity
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
Permalink
