The reconstitution of mammalian prion infectivity de novo.
The discovery of prion disease transmission in mammals, as well as a non-Mendelian type of inheritance in yeast, has led to the establishment of a new concept in biology, the prion hypothesis. The prion hypothesis postulates that an abnormal protein conformation propagates itself in an autocatalytic manner using the normal isoform of the same protein as a substrate and thereby acts either as a transmissible agent of disease (in mammals), or as a heritable determinant of phenotype (in yeast and fungus). While the prion biology of yeast and fungus supports this idea strongly, the direct proof of the prion hypothesis in mammals, specifically the reconstitution of the disease-associated isoform of the prion protein (PrP(Sc)) in vitro de novo from noninfectious prion protein, has been difficult to achieve despite many years of effort. The present review summarizes our current knowledge about the biochemical nature of the prion infectious agent and structure of PrP(Sc), describes potential strategies for generating prion infectivity de novo and provides some insight on why the reconstitution of infectivity has been difficult to achieve in vitro. Several hypotheses are proposed to explain the apparently low infectivity of the first generation of recently reported synthetic mammalian prions.
Baskakov
Ilia V
IV
Medical Biotechnology Center, Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA. Baskakov@umbi.umd.edu
D000682:Amyloid / Q000378:metabolism; D000818:Animals; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D017096:Prion Diseases / Q000235:genetics / Q000378:metabolism*; D011328:Prions / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D017433:Protein Structure, Secondary
D000682:Amyloid; D011328:Prions