Prion composition

Keywords Prion composition PMCA QuIC ASA Transmissible Spongiform Ecephalopathies... 

Since the development of the first PrP in vitro conversion reaction [2], much more efficient, continuous, and sensitive prion-seeded conversion assays have been developed. These techniques have been used to investigate prion composition and propagation mechanisms as well as prion strain and transmission barrier phenomena. Moreover, these reactions serve as bases for ultra-sensitive prion detection that should facilitate TSE diagnostic tests and screening assays for medical, agricultural and environmental prion contamination. 

The prion domains of Ure2p, Sup35p, and Rnqlp have unusual amino acid compositions, with abnormally high contents of the polar uncharged residues, Asn and Gin, and relatively low contents of charged and hydrophobic amino acids. In contrast, the amino acid composition of the HET-s prion domain is more typical of a normal globular protein. 

The [Het-s] system of P. anserina has some basic differences from the other systems (1) Its prion domain has a normal amino acid composition. 

The abnormal deposits found in the brains of CJD victims consist of an abnormal isoform of PrP. Prion protein is normally found in cells. Detailed structural studies show that normal cellular PrP (PrP ) is a soluble protein whose conformation is rich in a-helices with very little P-sheet. The PrP protein extracted from the brains of CJD victims (i.e., PrP ) is identical in primary amino acid sequence to the normal PrP (PrP ). However, PrP has a much greater content of P-sheet conformation with little a-helical structure. Thus PrP is neurotoxic because of its three-dimensional structure. When the prion protein is predominantly in an a-helical conformation it is nontoxic when the prion protein is predominantly in a P-sheet conformation, it kills neurons. The prion protein is thus made neurotoxic not by its amino acid composition but by its conformation. This concept is both fascinating and terrifying. Prion diseases are transmissible thus prions are infectious agents. However, prions are not like bacteria or viruses, or other infectious microbes—they are simply protein molecules. Prions are not microbes with cell membranes and nucleic acids they are not living things. Indeed, prions are not even infectious molecules, they are infectious molecular shapes. 

While the bias in the amino acid composition of yeast PrD sequences is now well established, the importance of the primary amino acid sequence for prion formation has been the subject of some debate. Several yeast PrDs (Sup35, Rnql, Newl) contain oligopeptide repeats that are important for efficient propagation of the prion form of that protein [108, 116, 117]. This is especially so for the yeast [PS/+] prion which possesses five imperfect nonapeptide repeats with a consensus sequence PQGGYQQYN (Fig. 6). This sequence bears a striking resemblance to the five octarepeats found in mammalian PrP and which have the consensus sequence PHGGGWGQ. 

Fig. 1. Reversed phase HPLC chromatogram of an endoproteinase Lys C digest of PrP 27-30, showing absorbance at 214 and 280 nm versus time (min). The gradient line shows acetonitrile content. The peptide compositions shown for each peak were derived from the experiments described in Section III. Peptides were identified containing all residues between 74 and 231, with the exception of an anticipated tetrapeptide, residues 107-110. (Reproduced with permission from Stahl, N. et al. in Prusiner, S.B., Collinge, J., Powell, J., and Anderton, B. [1992], Prion Diseases of Humans and Animals, pp. 361-379. Copyright Elsevier Science).

Finally, an important feature of prions in familial TSEs may he the stoichiometry and suhunit composition of PrP = isolated from affected individuals. Analysis of the allelic origin of the protease-resistant PrP oligomer isolated from patients with inherited prion diseases yielded different results for individual mutations. In the case of the mutations at positions 102,178,198, 200, and 217, only the mutant PrP forms pro-tease-resistant PrP = (Kitamoto et al, 1991 Tagliavini et al, 1994 Bar-banti etal, 1996 Gabizon etal, 1996 Chen etal, 1997). In contrast, the mutation at position 210 (Silvestrini et al, 1997) and also the insertion... 

Granic 1, Dolga AM, Nijholt IM, van Dijk G, Eisel UL (2009) Inflammation and NF-kappaB in Alzheimer s disease and diabetes. J Alzheimers Dis 16 809-821 Grossman A, Zeiler B, Sapirstein V (2003) Prion protein interactions with nucleic acid possible models for prion disease and prion fimction. Neurochem Res 28 955-963 Guan Z, Sdderberg M, Sindelar P, Pmsiner SB, Kristensson K, Dallner G (1996) Lipid composition in scrapie-infected mouse brain prion infection increases the levels of dolichyl phosphate and ubiquinone. J Neurochem 66 277-285... 

Brugger, B., Graham, C., Leibrecht, I., MombeUi, E., Jen, A., Wieland, F. and Morris, R. (2004) The membrane domains occupied by glycosylphosphatidyhnositol-anchored prion protein and Thy-1 differ in hpid composition. J. Biol. Chem. 279, 7530-7536. 

For a more detailed insight into disease progression the relative contributions of an increased p-sheet or a decreased a-helix (or both) to the observed phenomenon of scrapie-induced variations in p-sheet to a-helix ratios needed to be elucidated as well. Furthermore, investigations on animals sacrificed at different time points after peroral challenge had to be performed for additional information about the spatial and temporal course of protein composition and prion protein accumulation in scrapie infected nervous tissue during disease progression. 

Asou H, Hirano S, Uyemura K. Ganghoside composition of astrocytes. Cell Struct Func. 1989 14(5) 561-568. Nieznanski K. Interactions of prion protein with intracellular proteins so many partners and no consequences Cell Mol Neuwbiol 2010 30(5) 653-666. 

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