Cellular Biology of Prion Diseases

Abstract

Prion diseases are fatal neurodegenerative disorders of humans and animals that are important because of their impact on public health and because they exemplify a novel mechanism of infectivity and biological information transfer. These diseases are caused by conformational conversion of a normal host glycoprotein (PrPC) into an infectious isoform (PrPSc) that is devoid of nucleic acid. This review focuses on the current understanding of prion diseases at the cell biological level. The characteristics of the diseases are introduced, and a brief history and description of the prion hypothesis are given. Information is then presented about the structure, expression, biosynthesis, and possible function of PrPC, as well as its posttranslational processing, cellular localization, and trafficking. The latest findings concerning PrPSc are then discussed, including cell culture systems used to generate this pathogenic isoform, the subcellular distribution of the protein, its membrane attachment, proteolytic processing, and its kinetics and sites of synthesis. Information is also provided on molecular models of the PrPC→PrPSc conversion reaction and the possible role of cellular chaperones. The review concludes with suggestions of several important avenues for future investigation.

Specificity in the Cu2+ interactions with prion protein fragments and related His-rich peptides from mammals to fishes

“…However, despite the differ- [32][33][34][35] or PrP induced endocytosis resulting in transport copper from extracellular space to the cellular interior [16,36,37], copper buffering [38] copper sensing [39] and copper-reductase activity [40]. The substantial homology between the avian and mammalian versions of the prion proteins makes it likely that the conclusions concerning the biological functions might be similar to each other [41]. Chicken PrP similarly to mammalian PrP possesses repeated segment, with characteristic hexa-peptide-PHNPGY unit [29].…”

“…Species distribution profiles for Cu(II) complexes of Ac-(HNPGYP) 2 -NH 2 (left picture) and Ac-(HNPGYP) 4 -NH 2 (right picture) as well as their main complexes structures[41,43].…”

Role of the Cellular Prion Protein in the Neuron Adaptation Strategy to Copper Deficiency

“…The cell surface protein cellular prion protein (PrP C ), mostly expressed by neurons at synapses and gliocytes (Salès et al 1998;, is also believed to influence Cu uptake, since the binding of Cu 2? ions to its extracellular N-terminal domain stimulates the protein endocytosis, possibly providing a way for cell Cu entry (Pauly and Harris 1998;Perera and Hooper 2001;Harris 1999;Brown 2001). Inside the cell, Cu is delivered to proteins and organelles by specific Cu chaperons targeting it to Cu,Zn SODs (CCS), cytochrome c oxidase (COX17) and the cytosolic domain of Cu-ATPases ATP7A and ATP7B, responsible for Culoading onto cuproproteins in the Golgi apparatus and export of ion excess (Markossian and Kurganov 2003;Lutsenko and Petris 2002;Linz and Lutsenko 2007).…”

Interaction of Prion Protein with Small Highly Structured RNAs: Detection and Characterization of PrP-Oligomers

“…Under physiological conditions, PrP exists as a 30-35 kD monomer of predominantly a-helical secondary structure with anti-oxidant and anti-apoptotic properties [3]. Normal prion protein can undergo spontaneous [4][5][6] and facilitated [7,8] conformational changes to generate a pathogenic isoform (PrP sc ), which is considered to be a causative factor for a class of neurodegenerative conditions called prion diseases.…”