Pathologic Conformations of Prion Proteins

Abstract

While many aspects of prion disease biology are unorthodox, perhaps the most fundamental paradox is posed by the coexistence of inherited, sporadic, and infectious forms of these diseases. Sensible molecular mechanisms for prion propagation must explain all three forms of prion diseases in a manner that is compatible with the formidable array of experimental data derived from histopathological, biochemical, biophysical, human genetic, and transgenetic studies. In this review, we explore prion disease pathogenesis initially from the perspective of an autosomal dominant inherited disease. Subsequently, we examine how an intrinsically inherited disease could present in sporadic and infectious forms. Finally, we explore the phenomenologic constraints on models of prion replication with a specific emphasis on biophysical studies of prion protein structures. CONTENTS

Prion protein structure is affected by pH‐dependent interaction with membranes: A study in a model system

“…A first possibility is that the association of PrP with raft regions, maintaining the native secondary structure, may exert a protective effect on the protein after synthesis and delivery to the plasma membrane. Moreover, the protein unfolding and increase of oligomerization observed at acidic pH upon interaction with non-raft membranes may be viewed as an early step of the conversion to the aberrant pathogenic form [1], that could be triggered by interaction with endogenously formed or exogenously introduced PrPsc [27], or with chaperone molecules [28].…”

Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins?

“…The ability of these diseases to be transmitted, apparently by an abnormal form of the PrP, distinguishes them from the others discussed here, but there are also sporadic forms of human prion disease as well as forms that are purely genetic ; caused by mutations in the gene encoding PrP (CJD, GSS, and FFI). The disease-associated form of the PrP, or PrP-Sc, is resistant to proteolysis and rich in b-sheet structure, relative to the normal form of the PrP, PrP-C (Cohen & Prusiner, 1998). PrP-Sc can also be isolated in fibrous form (Rubenstein et al 1987).…”

Spreading of prions from the immune to the peripheral nervous system: a potential implication of dendritic cells

“…At the biochemical level, these diseases are characterized by the conversion of a normal cellular prion protein, PrP C , into an abnormal isoform, PrP Sc , which is enriched by -structures and is partially resistant to proteinase K (Cohen and Prusiner 1998). Prion-aVected nervous tissues show accumulation of PrP Sc , neuronal vacuolization and cell death in the central nervous system (CNS) (Bruce et al 1989).…”