18 Therapeutic Approaches to Prion Diseases

Abstract

Developing effective therapies for prion Diseases is a wonderful challenge. Once an effective therapy is devised, it will have important implications for many other degenerative diseases, some of which are thought to be disorders of protein processing like the prion diseases (Prusiner 2001). An effective therapy for any neurodegenerative disease would invigorate new efforts directed toward other disorders. The biology of prions is sufficiently advanced to make this a propitious time to develop therapeutically oriented research that might be extremely fruitful in the near future. Prion replication begins with protein synthesis, whereby the normal, cellular isoform of the prion protein (PrP C ) is translated in the endoplasmic reticulum and translocated through the Golgi as it transits to the cell surface. During this journey, PrP C is folded into a three-helix-bundle protein, which has a single disulfide bond, two Asn-linked oligosaccharides, and a glycosylphosphatidyl inositol (GPI) anchor. Both the complex-type oligosaccharides and the GPI anchor become sialyated, presumably as PrP traverses the Golgi. Throughout this process, the quality control machinery of the cell is operative to assure the PrP C that reaches the cell surface is properly folded and possesses the appropriate posttranslational modifications. Once PrP C reaches the cell surface, this protein seems to accumulate primarily in cholesterol-rich microdomains or rafts, where it can be converted into the disease-causing isoform (PrP Sc ). In principle, there are many potential targets for antiprion compounds to attack and thereby provide effective intervention. Superb mouse models of the genetic and infectious forms of prion disease recapitulate virtually every aspect...