Cross-Linking Cellular Prion Protein Triggers Neuronal Apoptosis in Vivo

Solforosi, Laura; Criado, José R.; McGavern, Dorian B.; Wirz, Sebastian; Sanchez‐Alavez, Manuel; Sugama, Shuei; DeGiorgio, Lorraine A.; Volpe, Bruce T.; Wiseman, Erika; Abalos, Gil C.; Masliah, Eliezer; Gilden, Donald H.; Oldstone, Michael B. A.; Conti, Bruno; Williamson, R. Anthony

doi:10.1126/science.1094273

Cited by 333 publications

(277 citation statements)

References 13 publications

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“…Many different antibodies are produced in response to active immunisation with an antigen, and it is possible that some of them exacerbate the neurodegenerative process rather than having beneficial effects. For example it has been recently reported that a specific monoclonal antibody can trigger rapid and extensive apoptosis in hippocampal and cerebellar neurons [102] or cerebral haemorrhage [103]. The mechanisms underlying the potentially adverse effects of amyloid immunotherapy are being very actively investigated and extensive research is under way to develop new vaccination strategies to enable beneficial effects to be achieved without undesirable side effects (for reviews see [94][95][96][97][98][99]104,105]).…”

Section: Therapeutic Reagentsmentioning

confidence: 99%

Probing the origins, diagnosis and treatment of amyloid diseases using antibodies

Dumoulin

Dobson

2004

Biochimie

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The deposition of proteins in the form of amyloid fibrils is the characteristic feature of more than 20 medical conditions affecting the central nervous system or a variety of peripheral tissues. These disorders, which include Alzheimer's disease, the prion diseases and type II diabetes, are of enormous importance in the context of present-day human health and welfare. Extensive research is therefore being carried out to define the molecular details of the mechanism of the pathological conversion of amyloidogenic proteins from their soluble forms into fibrillar structures. This review focuses on recent studies that demonstrate the power of using antibodies or antibody fragments to probe the process of fibril formation, and discusses the emerging potential of these species as diagnostic and therapeutic agents.

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Section: Therapeutic Reagentsmentioning

confidence: 99%

Probing the origins, diagnosis and treatment of amyloid diseases using antibodies

Dumoulin

Dobson

2004

Biochimie

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“…But, surprisingly, even here there is a debate as to the toxic or neutral effects of anti-PrP antibodies on neuronal viability, 59-61 before any action in relationship to Aβ is considered.…”

Section: Physiology Of Ion Channels Memory Deficitsmentioning

confidence: 99%

The P’s and Q’s of cellular PrP-Aβ interactions

Westaway

Jhamandas

2012

Prion

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“…It was previously reported that antibody-mediated crosslinking of PrP C at the cell surface leads to neurotoxicity 11 . However, both monovalent and divalent POM1, POM17 and POM19 derivatives (F(ab) 1 fragments, F(ab) 2 Fig.…”

mentioning

confidence: 99%

The toxicity of antiprion antibodies is mediated by the flexible tail of the prion protein

Sonati

Reimann

Falsig

et al. 2013

Nature

191

289

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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 1 and 3 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(Δ94-134), 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. (Fig. 1b). None of three high-affinity antibodies to the octapeptide repeats (OR, residues 50-90 embedded within the FT) were neurotoxic (Fig. 1b). Antibodies POM3 and D13, which bind the "charged cluster-2" 11 (CC2, residues 95-110), were innocuous at 67 nM but neurotoxic at 200 nM (Fig. 1b). None of the tested antibodies were toxic to Prnp o/o COCS ( Supplementary Fig. 2a). The identity of the targeted epitopes appeared to be a better predictor of PrP C antibody toxicity than their affinity to PrP C , suggesting that neurotoxicity resulted from the interaction of antibodies with specific PrP C domains (Supplementary Table 2).The mechanisms of neurotoxicity were further explored using POM1, a highly toxic antibody targeting the GD. Wild-type (wt) and tga20 COCS lost most granule cells (CGC) within 28 and 14 days post-exposure (dpe) to POM1, respectively (Fig. 2a-c). Controls included POM1-treated Prnp o/o COCS 12 , t...

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Cross-Linking Cellular Prion Protein Triggers Neuronal Apoptosis in Vivo

Cited by 333 publications

References 13 publications

Probing the origins, diagnosis and treatment of amyloid diseases using antibodies

Probing the origins, diagnosis and treatment of amyloid diseases using antibodies

The P’s and Q’s of cellular PrP-Aβ interactions

The toxicity of antiprion antibodies is mediated by the flexible tail of the prion protein

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