Which is more dangerous, the cellular (PrPc) or the infectious (PrPSc) prion protein? Until recently, this would have been easy to answer. But evidence is growing that the cellular variant may be just as toxic as the infectious one. In today’s Sciencexpress, Anthony Williamson at the Scripps Research Institute, La Jolla, California, together with colleagues there and elsewhere, report that simply crosslinking PrPc can turn it into a lethal weapon.

Most researchers agree that infectious prion protein confers a conformational change upon its cellular sibling. It is less clear which variant causes neurons to shrivel up and die. Recently, Susan Lindquist and colleagues showed that if the cell’s proteasome becomes overwhelmed, then a misfolded, normally innocuous cellular prion can become toxic even in the absence of PrPSc (see ARF related news story). Today’s report, too, seems to let PrPSc off the hook.

To test their hypothesis that PrPc signaling may underlie prion toxicity, first author Laura Solforosi and colleagues stereotaxically injected anti-prion antibodies into the hippocampus of live mice. They noticed extensive neuronal damage near the injection site. This damage could be caused by the procedure itself, or by an immune response, rather than an effect on prion signaling, but several observations suggest otherwise. Injection with a non-prion antibody failed to elicit the same response, as did injection with monovalent prion antibody, or with an antibody already saturated with the prion protein.

The idea that bringing two prions together causes toxicity comes from the nature of the antibodies that elicit the neuronal damage. In addition to divalent antibodies, Solforosi found that monovalent anti-prion antibodies worked equally well if effectively rendered divalent by separate antibodies against immunoglobulin light chains.

The toxicity seems to be mediated by apoptosis because TUNEL staining revealed many apoptotic neurons, the authors report. Antibodies placed in the cerebellar cortex also caused extensive neurotoxicity, suggesting that prion crosslinking could occur throughout the central nervous system.

The authors suggest that prions may pack a double punch. One comes when the cellular prion is co-opted by its infectious brethren, and the second hits through a dimerization-based apoptotic signaling pathway. The latter may explain why researchers were recently able to prevent and reverse prion disease by eliminating normal cellular prion protein (see ARF related news story). The authors also write that “extreme caution must be exercised if potent PrPc-specific antibody inhibitors of prion propagation are to be considered for use within the central nervous system.”—Tom Fagan.

Reference:
Solforosi L, Criado JR, McGavern DB, Wirz S, Sanchez-Alavez M, Sugama S, DeGiorgio LA, volpe BT, Wiseman E, Abalos G, Masliah E, Gilden D, Oldstone MB, Conti B, Williamson RA. Cross-linking cellular prion protein triggers neuronal apoptosis in vivo. Sciencexpress 2004 January 29. Abstract

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  1. In this intriguing article, Solforosi and coworkers show that intracerebral injection of certain anti-PrP monoclonal antibodies produce neuronal apoptosis. The author's interpretation is that crosslinking several molecules of PrPc with the antibody is responsible for this effect. The data provided is clean and the controls are appropriate.

    It would be interesting to investigate further the relationship of these findings to the disease process. One way to approach this would be to study in more detail whether the characteristics of neuronal damage induced by antibody crosslinking are the same as those produced by prion infection.

    An alternative interpretation for the need for crosslinking could be that certain antibodies produce a specific conformational change, or block the interaction of PrP with another protein (something that cannot be mimicked by the Fab fragment alone). Whether this is what happens during PrPSc-PrPc interaction is unknown, but is an interesting possibility to explore.

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References

News Citations

  1. Shape-Shifting Prion Protein in Cytosol: Highly Toxic Yet Almost Invisible
  2. A Potential Prion Therapy Focuses Attention on Protein Conversion

Paper Citations

  1. . Cross-linking cellular prion protein triggers neuronal apoptosis in vivo. Science. 2004 Mar 5;303(5663):1514-6. PubMed.

Further Reading

Papers

  1. . Cross-linking cellular prion protein triggers neuronal apoptosis in vivo. Science. 2004 Mar 5;303(5663):1514-6. PubMed.

Primary Papers

  1. . Cross-linking cellular prion protein triggers neuronal apoptosis in vivo. Science. 2004 Mar 5;303(5663):1514-6. PubMed.