Prion Protein (Prp) Fragments and Prion Disease Related Products

Definition
A prion is a proteinaceous infectious particle that lacks nucleic acid.

Discovery
Creutzfeldt-Jakob disease (CJD) remained a curious, rare neurodegenerative disease of unknown etiology for more than three score years. Only the transmission of CJD to apes by inoculation of brain extracts from patients who had died of CJD initiated a path of scientific investigation that was to demystify that fascinating area of biomedicine 1. In 1982 Prusiner had purified the hypothetical infectious prion, and that the infectious agent consisted mainly of a specific protein. Prusiner coined the word "prion" as a name for the infectious agent 2. While the infectious agent was named a prion, the specific protein that the prion was composed of is also known as the Prion Protein (PrP), though this protein may occur both in infectious and non-infectious forms.

Structural Characteristics
Prions are devoid of nucleic acid. The cellular prion protein (PrPC) is a sialoglycoprotein of Mr 33–35 kDa that is expressed predominantly in neurons. The normal cellular form of prion protein (PrPC) is a precursor to the pathogenic protease-resistant forms (PrPSc) believed to cause scrapie, bovine spongiform encephalopathy (BSE) and Creutzfeldt-Jakob disease 3. Its amino terminus contains the octapeptide PHGGGWGQ, which is repeated four times and is among the best-preserved regions of mammalian PrPC. PrPC is converted into PrPSc through a process whereby a portion of its a-helical and coil structure is refolded into ß-sheet. This structural transition is accompanied by profound changes in the physicochemical properties of the PrP. When the secondary structures of the PrP isoforms were compared by optical spectroscopy, they were found to be markedly different. Fourier transform infrared (FTIR) and circular dichroism (CD) spectroscopy studies showed that PrPC contains about 40% a helix and little ß sheet while PrPSc is composed of about 30% a helix and 45% ß sheet 4.

Mode of Action
Prions, the causative agents of prion diseases, consist of the abnormal isoform of prion protein, PrPSc. PrPSc is generated by conformational conversion of the normal isoform of prion protein, PrPC, a glycosyl-phosphatidyl-inositol-anchored glycoprotein abundantly expressed on the surface of neurons. Prions or PrPSc having invaded the body interact with PrPC and induce changes in structure of the interacting PrPC into that of PrPSc, leading to prion replication. At the same time, this constitutive conversion causes the detrimental accumulation of PrPSc in the brain tissue 5.

Functions
Neurotoxicity of a prion protein fragment: In transmissible and genetic neurodegenerative disorders such as scrapie of sheep, spongiform encephalopathy of cattle and Creutzfeldt–Jakob or Gerstmann–Sträussler–Scheinker diseases of humans, PrPSc accumulates in the central nervous system of affected individuals, and its protease-resistant core aggregates extracellularly into amyloid fibrils. The process is accompanied by nerve cell loss. Also there is a report that neuronal death results from chronic exposure of primary rat hippocampal cultures to micromolar concentrations of a peptide corresponding to residues 106–126 of the amino-acid sequence deduced from human PrP complementary DNA. DNA fragmentation of degenerating neurons indicates that cell death occurred by apoptosis. The PrP peptide 106–126 has a high intrinsic ability to polymerize into amyloid-like fibrils in vitro. These suggest that cerebral accumulation of PrPSc and its degradation products may play a role in the nerve cell degeneration that occurs in prion-related encephalopathies 6.

References
1. Gibbs CJ, Gajdusek DC, Asher DM, Alpers MP, Beck E, Daniel PM, Matthews WB. (1968). Creutzfeldt-Jakob disease (spongiform encephalopathy): transmission to the chimpanzee. Science, 161: 388–389.
2. Prusiner SB (1982). Novel proteinaceous infectious particles cause scrapie. Science, 216:136–144.
3. Brown DR, Qin K, Herms JW, Madlung A, Manson J, Strome R, Fraser PE, Kruck T, von Bohlen A, Schulz-Schaeffer W, Giese A, Westaway D, Kretzschmar H (1997). The cellular prion protein binds copper in vivo. Nature, 390(6661):684-687.
4. Pan KM, Baldwin M, Nguyen J, Gasset M, Serban A, Groth D, Mehlhorn I, Huang Z, Fletterick RJ, Cohen FE, Prusiner SB (1993). Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins. PNAS., 90:10962–10966.
5. Sakaguchi S (2007). Mechanisms of prion transmission. Nippon. Rinsho., 65(8):1391-1395.
6. Forloni G, Angerett N, Chiesa R, Monzani E, Salmona M, Bugiani O, Tagliavini F (1993). Neurotoxicity of a prion protein fragment. Nature, 362:543-546.