FORT LAUDERDALE, Fla. -- A voice that has been crying in thewilderness of skepticism for 20 years on Wednesday linkedAlzheimer's, Parkinson's and Lou Gehrig's diseases to the prionprotein.
Neurologist Stanley Prusiner of the University of California, SanFrancisco, spoke on "Molecular Genetics and Biology of PrionDiseases" at a session on Frontiers in Molecular Biology andHuman Diseases at the Miami Bio/Technology WinterSymposium here.
It's easier to tell what a prion is not than what it is. Thecontroversial pathogenic miniprotein is neither virus norviroid, neither bacterium nor fungus. Prions were first found inthe brains of sheep with scrapie, a fatal disease that afflictssheep and goats, and later in the brains of New Guineacannibals who ate the brains of their forebears and enemiesand died of kuru, a fatal neurosystem disorder. In the mid-1970s, a Nobel prize went to D. Carlton Gajdusek of the NationalInstitute of Neurologic Diseases and Stroke, who unraveled themystery of kuru.
"Kuru is now gone from the earth," Prusiner told his audience,but prions cause three other human neurodegenerativediseases: Creutzfeldt-Jakob, Gerstmann-Straussler-Scheinkerand fatal familial insomnia. Besides sheep scrapie, they causefive known animal diseases, notably spongiformencephalopathy (mad cow disease) in bovines. An epidemic ofthis last affliction has killed 130,000 cows in Great Britain sincethe late 1980s, Prusiner noted.
PrPc denotes the normal, non-pathogenic prion protein, whichis anchored to the cell surface by a glyco-inositol phospholipid.Its lethal form, PrPcs (the "s" is for scrapie) accumulates insidecells. It is also within the cell that the normal prion geneconverts to the lethal form. Prusiner said scientists have noidea what the normal protein's function is.
What is known is that human prion diseases are extremelyrare, with one to 10 cases reported per 100 million peopleworldwide. Prion diseases exist in both inherited andtransmissible forms -- that is familial and sporadic. Thissuggests to Prusiner that the prion pathology cannot simply becategorized as an infectious disease.
"The epidemiological search for an infectious etiology has gonefor naught," Prusiner told BioWorld in a post-session interview."More important, when wild-type PrP genes are overexpressedin transgenic mice, they contract the sporadic form of priondisease."
The excitement in prion research is currently centered ondevelopment of the gene's molecular genetic structure, whichconsists of four unstable alpha-helices surrounding a centralcore. They contain mutations and are prone to rearrangethemselves into more stable -- and possibly pathogenic -- flatbeta sheets.
"If one could learn to design a drug that fits in that core, thatwould stabilize those helices and prevent them from turninginto beta sheets," said Prusiner. It's too early to go for suchdrug discovery, he said. "We don't have enough informationyet. But that's the goal."
Prusiner does plan to obtain one basic piece of information. "Ina final experiment, I will try to convert the normal PrPc Prepgene into its pathogenic Prpcs form, and use it to infecttransgenic mice," he said. "This should end doubts about asecond molecule or chemical involved in prion activity."
Meanwhile, he holds up the prion knowledge gained andpublished during the past decade as providing "a model forstudying Alzheimer's, Parkinson's and ALS (amyotrophic lateralsclerosis). As he explained to BioWorld, Alzheimer's has fiveknown genes: APP, to which 5 percent of AD patients arelinked; an "anonymous" gene on chromosome 14, linked to 70percent; a putative gene in families that don't have the firsttwo; a susceptibility gene on chromosome 19 for APOE; and anunknown gene, which Prusiner said is probably expressed inolder people. This tends to parallel the prion pattern, includingrecent neuroanatomical data on prion pathology.
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.