Prions are infectious proteins that cause degeneration of the central nervous system (CNS). Prion diseases are disorders of protein conformation, the most common of which in humans is called Creutzfeldt-Jakob disease (CJD). CJD typically presents with dementia and myoclonus, is relentlessly progressive, and generally causes death within a year of onset. Most CJD patients are between 50 and 75 years of age; however, patients as young as 17 and as old as 83 have been recorded.
In mammals, prions reproduce by binding to the normal, cellular isoform of the prion protein (PrPC) and stimulating conversion of PrPC into the disease-causing isoform (PrPSc). PrPC is rich in α-helix and has little β-structure, while PrPSc has less α-helix and a high amount of β-structure (Fig. 383-1). This α-to-β structural transition in the prion protein (PrP) is the fundamental event underlying prion diseases (Table 383-1).
Structures of prion proteins. A. NMR structure of Syrian hamster recombinant (rec) PrP(90–231). Presumably, the structure of the α-helical form of recPrP(90–231) resembles that of PrPC. recPrP(90–231) is viewed from the interface where PrPSc is thought to bind to PrPC. Shown are: α-helices A (residues 144–157), B (172–193), and C (200–227). Flat ribbons depict β-strands S1 (129–131) and S2 (161–163). (A, from SB Prusiner: N Engl J Med 344:1516, 2001; with permission.) B. Structural model of PrPSc. The 90–160 region has been modeled onto a β-helical architecture while the COOH terminal helices B and C are preserved as in PrPC. (Image prepared by C. Govaerts.)
Table 383-1 Glossary of Prion Terminology |Favorite Table|Download (.pdf)
Table 383-1 Glossary of Prion Terminology
|Prion||Proteinaceous infectious particle that lacks nucleicacid. Prions are composed entirely of PrPSc molecules. They can cause scrapie in sheep and goats, and related neurodegenerative diseases of humans such as Creutzfeldt-Jakob disease (CJD).|
|PrPSc||Disease-causing isoform of the prion protein. Thisprotein is the only identifiable macromolecule in purified preparations of scrapie prions.|
|PrPC||Cellular isoform of the prion protein. PrPC is the precursor of PrPSc.|
|PrP 27-30||A fragment of PrPSc, generated by truncation of the NH2-terminus by limited digestion with proteinase K. PrP 27-30 retains prion infectivity and polymerizes into amyloid.|
|PRNP||PrP gene located on human chromosome 20.|
|Prion rod||An aggregate of prions composed largely of PrP 27-30 molecules. Created by detergent extraction and limited proteolysis of PrPSc. Morphologically and histochemically indistinguishable from many amyloids.|
|PrP amyloid||Amyloid containing PrP in the brains of animals or humans with prion disease; often accumulates as plaques.|