By David N. Leff
Ask a prion disease researcher how the infectious particle infects its host victim. The answer will likely be:
A normal prion protein, PrP, turns pathogenic by changes in its basic molecular shape. This abnormal, malformed switch from Jekyll to Hyde is protease-resistant, so the particle acquired the designation, PrPres. It replicates by inducing is recipient organism to take on the abnormal prion conformation.
As such, it's the infectious agent in all of the transmissible spongiform encephalopathies (TSE), from the bovine form, BSE, to the predominant human equivalent, Creutzfeldt-Jakob disease. (see related article on p. 1.)
That scenario defines the prevailing "prion hypothesis."
French findings, reported in today's issue of Science, dated Jan. 16, 1997, challenge that doctrine. The paper's suggestive title: "Transmission of the BSE agent to mice in the absence of detectable abnormal prion protein."
Neurovirologist and veterinary surgeon Corinne Lasmezas is the paper's first author.
"What we saw in our experiments," she told BioWorld Today, "was that the abnormal prion agent may be able to replicate in its recipient animal without inducing accumulation of the prion protein's abnormal form."
She and her co-authors at the French Atomic Energy Commission's Neurology Branch, In Fontenay-aux-Roses, injected a homogenate of brain tissues from British BSE cattle directly into the brains of 30 mice.
Within 368 to 719 days, all of the inoculated animals had symptoms of a neurological disease * hind limb paralysis, tremors, hypersensitivity to stimulation, apathy, hunched posture. And their brains revealed neuronal death.
Yet, the brain tissue in 55 percent of those 30 mice showed no signs of PrPres, the designated hitter of prion infectivity. They were devoid of spongiform vacuolation, the hallmark of TSE. Nevertheless, they were able to transmit the infection.
A second set of mice got cerebral inoculation with brain material from both the PrPres-positive and negative cohorts among the initial 30. Most of them developed the classical disease, but with markedly shorter incubation periods.
A third passage reduced incubation times still further, and all but eliminated the animals lacking the infectious PrPres protein.
Thus, said Lasmezas, putting a new twist on the prion doctrine, "PrPres is clearly involved in the pathogenic process of TSEs. However, it may not be the transmissible component of the infectious agent."
Her group is now "investigating the role of the normal prion protein. Is it, for example, a receptor of the agent? Or what is its role?"
She concluded: ""If we can infect PrP normal mice with the nucleic-acid-like agent we have identified in our work, it would mean that the role of PrP is not what has been taught until now. But that's just getting under way in our lab." *