Thematic series on prions

Cover of the JBC thematic minireview series on Prions
More than 30 years ago, Stanley Prusiner at the University of California, San Francisco, coined the term “prion” and began to develop evidence to support his radical hypothesis for a new kind of infectious agent.
 
Since then, the prion hypothesis — that scrapie, a fatal neurodegenerative disease in sheep and goats, is caused by a misfolded protein devoid of a genomic component — has been proved. The new dogma that resulted has been fruitful for guiding new approaches to studying Alzheimer’s and Parkinson’s diseases. In addition, emerging biochemical details of the pathogenesis of misfolded proteins are beginning to provide potential targets for therapy.
 
In a new thematic minireview series in the Journal of Biological Chemistry, Prusiner and other researchers cover prion replication, transmission and neurotoxicity. JBC Associate Editor Paul Fraser of the University of Toronto oversaw the series.
 
In the first minireview, Joel C. Watts and Prusiner, both of UCSF, discuss the importance of mouse models for studying pathogenesis of prion diseases and developing new therapies. Transgenic mice that overexpress the prion protein, known as PrP, develop clinical signs of disease in less than half the time it takes for normal mice. So-called knock-in mice, in which the normal PrP gene is replaced with a mutant PrP gene, have been used to study pathogenesis of mutations associated with sporadic and genetic human prion diseases. The authors review the drawbacks and limitations of using mouse models to study Alzheimer’s and Parkinson’s diseases, considered to be prionlike diseases, and predict that the next generation of research may rely on transgenic rats. Rats may be better suited for studying human neurological diseases because of their more complex behaviors and larger brain sizes.
 
Surachai Supattapone of the Geisel School of Medicine at Dartmouth University summarizes, in the second minireview, studies with synthetic prions and the enhancement of infectivity with cofactors. Supattapone writes, “Recently, synthetic prions with a high level of specific infectivity have been produced from chemically defined components in vitro.” These biochemical studies, he emphasizes, provide formal proof that prions are indeed infectious agents lacking a nucleic acid genome and elucidate the roles of the cofactor molecules — such as phosphatidylenthanolamine and RNA — in the propagation and maintenance of infectious prions. Furthermore, Supattapone writes, cofactor molecules “influence strain properties by facilitating specific PrPSc conformations.”
 
In the third minireview, Marc I. Diamond and Brandon Holmes of Washington University in St. Louis review the studies of the prionlike tau protein associated with Alzheimer’s disease. Several proteins implicated in the development of Alzheimer’s have been shown to aggregate and spread to neighboring brain cells. Although these proteins, notably tau and alpha synuclein, are distinctly different from prion protein, they can undergo conformational changes leading to aggregation and the formation of fibrils in a prionlike manner. Several recent studies have detected the spread of tau aggregates between cells in vivo and in vitro. The ability of tau aggregates to move across synapses could explain the involvement of neural networks in neurodegenerative diseases, the authors say, and interruption of the cell-to-cell propagation of protein aggregates could provide therapeutic benefits. Studies evaluating potential therapies target secretion, clearance or uptake of tau aggregates.
 
In the final minireview in the series, Giovanna R. Malucci, Mark Halliday and Helois Radford examine how prion generation and spread affects neurotoxicity. Prion diseases, including scrapie, Creutzfeld–Jakob Disease and bovine spongiform encephalopathy (mad cow disease), are transmissible and fatal. In these diseases, prion protein is the infectious agent, and accumulation of prion aggregates leads directly to neurotoxicity and eventual death. In Alzheimer’s and Parkinson’s, other proteins — including amyloid-beta, tau and alpha-synuclein — aggregate and propagate throughout the brain; however, the spread of these misfolded protein aggregates is not linked clearly to neurodegeneration. Some studies using mouse models of scrapie have found a dissociation between prion replication and neurotoxicity. What is the relationship between prion propagation and toxicity? The authors of this minireview focus on the unfolded protein response, “a protective cellular mechanism that is induced during periods of cellular and endoplasmic reticulum stress, which aims to maintain protein-folding homeostasis with the ER.” Therapeutic manipulation of the unfolded protein response, the authors note, appears to provide neuroprotection in animal models.
Thomas E. SchindlerThomas E. Schindler (tschindler.phd@gmail.com) earned a Ph.D. in immunology from the University of Illinois Medical Center in 1981. After a postdoctoral stint at Memorial Sloan–Kettering Cancer Center, he joined Xytronyx, a small biotech company in San Diego started by his graduate adviser, Peter Baram. He took a year off in 1992 to move back east and become a high-school science teacher. Since early retirement from full-time teaching in 2007, he has taught biology and microbiology in nearby community colleges. Now he is pursuing a new career: science writing.