30 January 2004. 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.
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