A Trans-dominant Negative 37 kDa/67 kDa Laminin Receptor Mutant Impairs PrPSc Propagation in Scrapie-infected Neuronal Cells

Vana, Karen; Weiß, Stefan

doi:10.1016/j.jmb.2006.02.011

Cited by 32 publications

(34 citation statements)

References 26 publications

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“…23 Secretion of a transdominant negative LRP mutant also abolishes PrP Secretion of a transdominant negative LRP mutant also abolishes PrP Sc propagtion in neuronal cells. 24 � polyclonal anti-LRP/LR antibody termed W3 interferes with PrP27-30 cell binding 21 and internalization of bovine PrP Sc by human enterocytes. .…”

Section: Introductionmentioning

confidence: 99%

Anti-LRP/LR Antibody W3 Hampers Peripheral PrPSc Propagation in Scrapie Infected Mice

Zuber

Mitteregger²,

Pace³

et al. 2007

Prion

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Key WordS37kDa/67kDa laminin receptor, LRP/LR, prion, PrP, TSE-therapy AbbrevIAtIonS CJDCreutzfeldt AbStrACtWe identified the 37kDa/67kDa laminin receptor (LRP/LR) as a cell surface receptor for the cellular prion protein (PrP c ) and the infectious prion protein (PrP Sc ). Recently, we showed that anti-LRP/LR antibody W3 cured scrapie infected N2a cells. Here, we demonstrate that W3 delivered by passive immunotransfer into C57BL/6 mice reduced the PrP Sc content in the spleen significantly by 66%, demonstrating an impairment of the peripheral PrP Sc propagation. In addition, we observed a 1.8-fold increase in survival of anti-LRP/LR antibody W3 treated mice (mean survival of 31 days) compared to preimmune serum treated control animals (mean survival of 17 days). We conclude that the significant effect of anti-LRP/LR antibody W3 on the reduction of peripheral PrP Sc propagation might be due to the blockage of the prion receptor LRP/LR which is required, as previously shown in vitro, for PrP Sc propagation in vivo.

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Section: Introductionmentioning

confidence: 99%

Anti-LRP/LR Antibody W3 Hampers Peripheral PrPSc Propagation in Scrapie Infected Mice

Zuber

Mitteregger²,

Pace³

et al. 2007

Prion

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“…LRP/LR attracts more and more attention as a target for therapy in prion diseases and cancer. Multiple strategies on LRP inactivation have been shown to be successful by inhibiting PrP Sc propagation in vitro: (i) downregulation of LRP via antisense or siRNA strategies completely blocks PrP Sc propagation (Leucht et al, 2003) and delays the incubation time in scrapie-infected mice (H. Ludewigs and others, unpublished data), (ii) a trans dominant-negative LRP mutant interferes with PrP Sc propagation in ScN2a cells (Vana & Weiss, 2006) Sc propagation significantly by 66 % and prolongs the survival in scrapie-infected mice by 1.8-fold (Zuber et al, 2007b). Many of these anti-LRP/LR tools particularly antibodies, siRNAs and polysulfated glycanes interfere with the laminin-LRP/LR interaction, which results in a reduced invasive potential of neoplastic cells, recommending these tools as powerful therapeutic agents in the treatment of cancer, especially metastasis formation (Zuber et al, 2008b).…”

mentioning

confidence: 99%

“…LRP/LR attracts more and more attention as a target for therapy in prion diseases and cancer. Multiple strategies on LRP inactivation have been shown to be successful by inhibiting PrP Sc propagation in vitro: (i) downregulation of LRP via antisense or siRNA strategies completely blocks PrP Sc propagation (Leucht et al, 2003) and delays the incubation time in scrapie-infected mice (H. Ludewigs and others, unpublished data), (ii) a trans dominant-negative LRP mutant interferes with PrP Sc propagation in ScN2a cells (Vana & Weiss, 2006), (iii) polysulfated glycanes block the PrP Sc -LRP/LR interaction and strongly reduce PrP Sc binding (Gauczynski et al, 2006) and (iv) the anti-LRP antibody, W3, abrogates PrP Sc accumulation in scrapieinfected cells (Leucht et al, 2003) and prevents binding and internalization of PrP BSE prions (Morel et al, 2005). W3 reduces peripheral PrP Sc propagation significantly by 66 % and prolongs the survival in scrapie-infected mice by 1.8-fold (Zuber et al, 2007b).…”

mentioning

confidence: 99%

Delivery of single-chain antibodies (scFvs) directed against the 37/67 kDa laminin receptor into mice via recombinant adeno-associated viral vectors for prion disease gene therapy

Zuber¹,

Mitteregger²,

Schuhmann

et al. 2008

Journal of General Virology

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The 37/67 kDa laminin receptor (LRP/LR) acts as a receptor for prions providing a promising target for the treatment of prion diseases. Recently, we selected anti-LRP/LR single-chain antibodies (scFvs) and proved a reduction of the peripheral PrP Sc propagation by passive immunotransfer into scrapie-infected mice. Here, we report the development of an in vivo gene delivery system based on adeno-associated virus (AAV) vectors expressing scFvs-S18 and -N3 directed against LRP/LR. Transduction of neuronal and non-neuronal cells with recombinant (r)AAV serotype 2 vectors encoding scFv-S18, -N3 and -C9 verified the efficient secretion of the antibodies. These vectors were administered via stereotactic intracerebral microinjection into the hippocampus of C57BL/6 mice, followed by intracerebral inoculation with 10 % RML at the same site 2 weeks post-injection of rAAV. After 90 days post-infection, scFv-S18 and -N3 expression resulted in the reduction of peripheral PrP Sc propagation by approximately 60 and 32 %, respectively, without a significant prolongation of incubation times and survival. Proof of rAAV vector DNA in spleen samples by real-time PCR strongly suggests a transport or trafficking of rAAV from the brain to the spleen, resulting in rAAV-mediated expression of scFv followed by reduced PrP Sc levels in the spleen most likely due to the blockage of the prion receptor LRP/LR by scFv.Prion diseases are fatal lethal neurodegenerative diseases affecting humans and animals (for review see Weissmann, 2004;Zuber et al., 2007a). None of the affected individuals can be treated or cured effectively (Ludewigs et al., 2007;Vana et al., 2007;Weissmann & Aguzzi, 2005). The abnormal form of the prion protein, PrP Sc , is frequently associated with infectivity and propagates mainly in the brain and the lymphoreticular system (LRS). Accumulation of the aggregated PrP Sc leads to neuronal death. PrP Sc is distinct from the host protein PrP c by its biochemical properties such as proteinase K sensitivity and insolubility, but harbours the same amino acid sequence. The generation of PrP Sc from PrP c involves conformational changes accompanied by modifications in the secondary structure of the protein (for review see Aguzzi & Weissmann, 1998;Prusiner, 1998;Weissmann, 2004).The 37/67 kDa laminin receptor (LRP/LR) is a multifunctional protein (i) playing an important role in cell adhesion, movement and growth of many cell types, (ii) acting as a receptor for some subtypes of adeno-associated 3These authors contributed equally to this work. (Morel et al., 2005). The fact that LRP levels are increased in organs of the LRS and central nervous system (CNS), such as spleen and brain, of infected animals (Rieger et al., 1997) strongly suggests that this receptor is not only essential for prion uptake after oral infection but also plays an important role for PrP Sc propagation and prion pathogenesis in the peripheral nervous system, including the LRS and CNS. Additionally, several laminin receptor isoforms have been found in mouse bra...

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“…Recently, it has been shown that a LRP mutant encompassing only the extracellular domain of LRP/LR (LRP102-295::FLAG) might act in a transdominant negative manner as a decoy by trapping PrP molecules (Vana and Weiss, 2006). In vitro studies revealed that the LRP mutant is able to reduce the PrP Sc accumulation in scrapie-infected neuronal cells (Vana and Weiss, 2006) and, thus, might have potential for the development of a TSE therapy.…”

Section: Transdominant Negative Lrp Mutantsmentioning

confidence: 99%

Novel Aspects of Prions, Their Receptor Molecules, and Innovative Approaches for TSE Therapy

et al. 2006

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1. Prion diseases are a group of rare, fatal neurodegenerative diseases, also known as transmissible spongiform encephalopathies (TSEs), that affect both animals and humans and include bovine spongiform encephalopathy (BSE) in cattle, scrapie in sheep, chronic wasting disease (CWD) in deer and elk, and Creutzfeldt-Jakob disease (CJD) in humans. TSEs are usually rapidly progressive and clinical symptoms comprise dementia and loss of movement coordination due to the accumulation of an abnormal isoform (PrP(Sc)) of the host-encoded prion protein (PrP(c)). 2. This article reviews the current knowledge on PrP(c) and PrP(Sc), prion replication mechanisms, interaction partners of prions, and their cell surface receptors. Several strategies, summarized in this article, have been investigated for an effective antiprion treatment including development of a vaccination therapy and screening for potent chemical compounds. Currently, no effective treatment for prion diseases is available. 3. The identification of the 37 kDa/67 kDa laminin receptor (LRP/LR) and heparan sulfate as cell surface receptors for prions, however, opens new avenues for the development of alternative TSE therapies.

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A Trans-dominant Negative 37 kDa/67 kDa Laminin Receptor Mutant Impairs PrPSc Propagation in Scrapie-infected Neuronal Cells

Cited by 32 publications

References 26 publications

Anti-LRP/LR Antibody W3 Hampers Peripheral PrPSc Propagation in Scrapie Infected Mice

Anti-LRP/LR Antibody W3 Hampers Peripheral PrPSc Propagation in Scrapie Infected Mice

Delivery of single-chain antibodies (scFvs) directed against the 37/67 kDa laminin receptor into mice via recombinant adeno-associated viral vectors for prion disease gene therapy

Novel Aspects of Prions, Their Receptor Molecules, and Innovative Approaches for TSE Therapy

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