Prion Protein's Role Revealed Cellular prion protein (PrP), a naturally occurring protein found on surfaces of nerve cells in the brain, is known to be able to convert into a structural form associated with transmissible spongiform encephalopathies (TSEs)—diseases such as scrapie in sheep, mad cow disease in cattle, and Creutzfeldt-Jakob disease in people. But despite long-standing efforts, researchers have not been able to determine the normal role this important protein plays in the brain. A French research group has now overcome that hurdle,findingthat PrP is a component of a cell-signaling pathway [Science, 289, 1925 (2000)]. The team was made up of graduate student Sophie Mouillet-Richard and Director Odile Kellermann of the Laboratory of Cellular Differentiation at Pasteur Institute, Paris; Jean-Marie Launay, head of the biochemistry laboratory at Lariboisiere Hospital, Paris; and coworkers. In the signaling process, PrP interacts with a protein called caveolin-1 and then activates a tyrosine kinase called Fyn. A protein called clathrin may also be involved in the pathway, but that's uncertain at this point. The overall function of this signaling pathway is still not known, but its discovery should help researchers attain a better understanding of PrPc and its role in TSEs. "Everybody suspected that PrP was a signaling protein, but nobody really predicted it. There is no question that this is thefirstclear-cut evidence of signal transduction by PrPc," comments Adriano Aguzzi, a professor of neuropathology at University Hospital, Zurich, who specializes in neurodegenerative diseases. A direct route to the function of a protein is to determine the effects of the protein's absence in "knockouts"— organisms genetically engineered to be incapable of expressing the protein. But when researchers developed PrP c knockout mice, they were surprised to find that the mice developed normally and exhibited only relatively minor neurological problems. These experiments thus left the protein's function unclear. A few years ago, a group led by neuropathology professor Hans A. Kretzschmar, now at Ludwig Maximilians University, Munich, Germany, hypothesized that the role of PrP might have something to do with copper transport or
storage. The researchers showed that PrP binds Cu2+ Prion protein is involved in and that the nerve cells of signaling pathway PrP knockout mice had abnormally low levels of copSignal? per. But thefindingsdid not provide any definitive evidence for such a functional role. Cellular prion protein (PrPc) In the current study, the Neuron cell French researchers began membrane with the assumption that PrP was a signaling protein. Using specific antibodies to PrP to mimic the activity of a putative endogenous activator, they found that activated PrP interacts with caveolin-1 and that this comSignaling plex passes the signal along cascade to Fyn. Because PrPc is exControl of pressed on the outside and neuronal functions caveolin-1 and Fyn on the inside of neuronal membranes, Aguzzi believes an as-yet-unidentified membrane-spanning larger signal transduction cascade, and molecule may serve as a signaling interme- they do not yet know the pathway's overdiary between PrP and caveolin-1 and all function. But Kellermann tells C&EN Fyn. "I would love to learn what is the miss- her current best guess is that it might ining link, because topological^ there is sim- volvefinecontrol of neuronal homeostaply no way PrP and Fyn talk to each other sis. She hopes future work by her group directly," he says. will eventually be able tofillin this and Indeed, the French scientists believe other details on PrP signaling. they have found only a small part of a Stu Borman
Invest In R&D Now, Profit Later Ask any chemist. He or she likely will attest that investing in R&D pays off in new knowledge, increased sales and licensing for firms, and improved and less expensive products for consumers. Yet that view is based as much on gut feeling as on solid data. But an effort to quantify the value of chemical innovation is beginning to show that R&D investments do indeed deliver significant bang for the buck. Initial results from a study commissioned by the Council for Chemical Research (CCR) were Lev presented last week at its annual meeting in New Orleans. The effort began just a year ago after Richard M. Gross, corporate vice president for R&D at Dow Chemical and CCR's sec-
ond vice chair, articulated the need for a more quantitative understanding of the impact of chemical research. "We are all researchers," Gross said of CCR's members from academia, industry, and government "It's troubling that the only data we've had about the value of research has been qualitative and anecdotal, just 'high-tech storytelling/ " he told C&EN. One component of the multifaceted study focuses on the productivity of chemical R&D. Baruch Lev, professor of accounting and finance at New York University's School of Business, reported that the return to chemicalfirmsfromthe money they invest in R&D is "really high—I was surprised by the numbers." SEPTEMBER 18,2000 C&EN
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