The role of prion protein conformers in prion disease

Lingappa, Vishwanath

Abstract

The prion protein (PrP) is a conserved glycoprotein of vertebrates that is involved in a group of spongiform neurodegenerative disorders, collectively termed prion diseases, some of which pose a substantial and currently unmet public health hazard around the globe. Hence a better understanding of PrP's role in prion disease pathogenesis is paramount. ? ? Prion diseases include overlapping sets of disorders that vary as to whether, and to what degree, they are inherited (genetic), infectious (transmissible), or seemingly spontaneous (sporadic) in etiology. These diverse manifestations suggest that important relationships between PrP and other genes involved in the development, maintenance, or function of the nervous system remain to be elucidated. Thus, the study of prion disease pathogenesis may be a powerful probe of otherwise currently intractable dimensions of neurobiology. ? ? PrP has also been of interest because of its remarkable biogenesis. Initially homogeneous nascent PrP chains are synthesized as distinctive forms, termed conformers that are identical in primary amino acid sequence but different in both transmembrane topology and intrinsic folding. A complex machinery has been implicated in the genesis of two of the PrP conformers, termed SecPrP and CtmPrP, and a surprising role for signal sequences in directing this process has been identified. ? ? Independent lines of inquiry converged with the demonstration that the unusual features of PrP biogenesis are central to its role in genetic prion disease. From studies carried out over the past 4 years with support of the present grant, major progress has been made in understanding the conformer termed PrP, and its role in prion disease pathogenesis. In particular it has been established that CtmPrP also plays a crucial role in infectious as well as genetic prion disease and brings about neurodegeneration by triggering a pathway of apoptosis. Furthermore, powerful model systems, including cell culture and Tg mice that reproduce key features of prion disorders, have been developed and are beginning to be used for dissection of the disease-associated apoptotic pathway involving CtmPrP. ? ? In part as a result of the progress in the present grant period, important new questions regarding CtmPrP and other PrP conformers have emerged. In this renewal application we propose to build on our previous studies, utilizing the full range of tools and reagents that we have developed over the past four years, for the study of PrP conformers in disease. Based on our recent demonstration of their utility in detection of individual conformers, we will also generate conformer-specific mAbs optimized for immunocytochemistry. Using these tools we will: i) corroborate the Ctm index in other model systems of prion disease and explore the possibility of variations on this theme in triggering or suppressing apoptosis; ii) elucidate the precise interactions by which CtmPrP triggers apoptosis; iii) address the role of posttranslational modifications of PrP conformers in prion disease, including the putative role of cleavage of the signal peptide as a regulator of conformer production/export, iv) attempt to detect NtmPrP and explicate its role, if any, in prion disease, and v) identify the signaling pathway(s) by which PrPSc appears to trigger CtmPrP production. ? ? Through these studies, an ongoing fruitful line of investigation with regards to PrP-mediated neurodegeneration will be extended, providing a greater degree of clarity and precision with regards to the role of CtmPrP, SecPrP, and NtmPrP in prion disease. In addition, exciting new directions regarding the regulation of PrP conformers will be explored, setting the stage for the development of potential therapeutic modalities based on enhanced or suppressed production and maturation of PrP conformers. ? ?