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

Vana, Karen; Zuber, Chantal; Nikles, Daphne; Weiß, Stefan

doi:10.1007/s10571-006-9121-1

Cited by 51 publications

(37 citation statements)

References 179 publications

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“…LPB-p40 was localized on 40S ribosomes [7] and in the nucleus [8], while 67LR was located on the cell surface, where, in addition to its role as a high affinity laminin receptor, it was shown to function as the receptor for elastin [9] and as a positional marker for the differentiation of the fetal eye organ [10]. 37-kDa LRP was identified as a PrP c accomplice [11], and 37LBP/67LR acts as a receptor for PrP c [12] and infectious prions [13], as extensively reviewed elsewhere [14][15][16]. Additionally, 37LBP/67LR acts as a receptor for a number of viruses, including sindbis [17], dengue [18], and the adeno-associated virus serotypes 8, 2, 3, and 9 [19].…”

Section: Introductionmentioning

confidence: 99%

siRNA-mediated silencing of the 37/67-kDa high affinity laminin receptor in Hep3B cells induces apoptosis

Susantad

Smith

2008

Cellular and Molecular Biology Letters

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Abbreviations used: GAPDH -glyceraldehyde 3-phosphate dehydrogenase; LBP-p40 -laminin-binding protein precursor p40; LRP -laminin receptor precursor; PrP c -cellular prion protein; siRNA -small interfering RNAs; 37LBP -37-kDa laminin binding protein; 67LR -67-kDa laminin receptor However, few studies have investigated the cellular consequence of the ablation of this gene's expression. To address this issue, the expression of the 37/67-kDa high affinity laminin receptor was knocked out with several siRNA constructs via RNA interference in transformed liver (Hep3B) cells. In each case where the message was specifically ablated, apoptosis was induced, as determined by annexin V/propidium iodide staining, and by double staining with annexin V and an antibody directed against the 37/67-kDa high affinity laminin receptor. These results suggest that this protein plays a critical role in maintaining cell viability.

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Section: Introductionmentioning

confidence: 99%

siRNA-mediated silencing of the 37/67-kDa high affinity laminin receptor in Hep3B cells induces apoptosis

Susantad

Smith

2008

Cellular and Molecular Biology Letters

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“…12 Besides monoBesides monoclonal antibodies targeting the prion protein, 13,14 also single chain anti-PrP antibodies are currently investigated for a TSE therapy. 15 �mong many interaction partners identified for PrP c , 10,[16][17][18] the non-integrin 37/67 kDa laminin receptor (LRP/LR) has been discovered as a receptor for both the cellular PrP c 19,20 and the disease associated PrP Sc . 21,22 Downregulation of LRP/LR by antisense Downregulation of LRP/LR by antisense LRP RN� or siRN�s directed against LRP mRN� abrogates PrP Sc propagation in ScN2a cells.…”

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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“…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).…”

mentioning

confidence: 99%

“…We recently showed that blockage or downregulation of LRP/LR in neoplastic cells prevents invasion of these cells, suggesting that LRP/LR plays a major role in cancer metastasis (Zuber et al, 2008b) and (iv) finally, LRP/LR represents a key player in prion infection (Ludewigs et al, 2007;Vana et al, 2007;Zuber et al, 2007a). LRP has been shown to act both as the PrP c (Gauczynski et al, 2001b) and PrP Sc receptor (Gauczynski et al, 2006) and is responsible for bovine PrP Sc internalization by human enterocytes (Morel et al, 2005).…”

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

Cited by 51 publications

References 179 publications

siRNA-mediated silencing of the 37/67-kDa high affinity laminin receptor in Hep3B cells induces apoptosis

siRNA-mediated silencing of the 37/67-kDa high affinity laminin receptor in Hep3B cells induces apoptosis

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

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