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Prionkrankheiten

Prionkrankheiten oder transmissible spongiforme Enzephalopathien (TSE) sind eine spezielle Gruppe von neurodegenerativen Erkrankungen. Sie treten beim Menschen - Creutzfeldt-Jakob-Krankheit (CJD für "Creutzfeldt-Jabob disease") sowie bei Tieren - u.a. "Scrapie" bei Schaf,  "bovine spongiform encepahlophathy" (BSE) bei Rindern auf. Prionkrankheiten können einen spontanen, genetischen oder infektiösen Hintergrund haben. Die Übertragbarkeit durch Infektion unterscheidet Prionkrankheiten von anderen neurodegenerativen, wie z.B. die Alzheimersche Demenz oder Chorea Huntington. Im Krankheitsverlauf  treten Verhaltensänderungen, koordinative Fehlfunktionen (Ataxie) und Demenz auf neuropathologisch sind schwammartige (spongiforme) Änderungen im Gehirn, Degeneration von Neuronen und Astrocytose als histopathologische Kennzeichen von Prionkrankheiten nachweisbar (Abb. 1).

1982 veröffentlichte Stanley B. Prusiner die Prion-Hypothese, welche besagt, dass der Erreger der Prionkrankhieten ausschließlich aus proteinösen Partikeln (Prionen) bestand. Der Hauptbestandteil der Prionen ist das Prion Protein in einer fehlgefalteten Struktur (PrPSc). Das Prion Protein ist ein köpereigenes Protein (PrPC). Der Replikationsmechanismus beruht darauf, dass PrPSc in der Lage ist mit PrPC zu interagieren und PrPC in PrPSc zu überführen.


Wir entwickeln eine Methode zu frühen Diagnose von Prionkrankheiten, indem wir den Aggregationszustand als Biomarker nutzen.

Zusätzlich untersuchen wir den zugrunde liegenden Replikationsmechanismus in vitro.

Publikationen

  • Gomes CM, Hoyer W, Luo J 
    Editorial: The Biochemistry of Amyloids in Neurodegenerative Diseases, Volume I 
    Front Neurosci 15, 819481 (2021) 
    https://doi.org/10.3389/fnins.2021.819481  
  • König AS, Rösener NS, Gremer L, Tusche M, Flender D, Reinartz E, Hoyer W, Neudecker P, Willbold D, Heise H 
    Structural details of amyloid β oligomers in complex with human prion protein as revealed by solid-state MAS NMR spectroscopy 
    J Biol Chem 296, 100499 (2021) 
    https://doi.org/10.1016/j.jbc.2021.100499  
  • Willbold D, Strodel B, Schröder GF, Hoyer W, Heise H 
    Amyloid-type protein aggregation and prion-like properties of amyloids 
    Chem Rev 121, 8285-8307 (2021) 
    https://doi.org/10.1021/acs.chemrev.1c00196  
  • Rösener NS, Gremer L, Wördehoff MM, Kupreichyk T, Etzkorn M, Neudecker P, Hoyer W 
    Clustering of human prion protein and α-synuclein oligomers requires the prion protein Nterminus 
    Commun. Biol. 3, 365 (2020) 
    https://doi.org/10.1038/s42003-020-1085-z  
  • Rösener NS, Gremer L, Reinartz E, König A, Brener O, Heise H, Hoyer W, Neudecker P, Willbold D 
    A d-enantiomeric peptide interferes with heteroassociation of amyloid-β oligomers and prion protein 
    J. Biol. Chem. 293, 15748-15764 (2018) 
    https://doi.org/10.1074/jbc.RA118.003116  
  • Victor J, Steger G, Riesner D 
    Inability of DNAzymes to cleave RNA in vivo is due to limited Mg2+ concentration in cells 
    Eur Biophys J 47, 333-343 (2017) 
    https://doi.org/10.1007/s00249-017-1270-2  
  • Müller H, Brener O, Andreoletti O, Piechatzek T, Willbold D, Legname G, Heise H 
    Progress toward structural understanding of infectious sheep PrP-amyloid 
    Prion 8, 344-358 (2014) 
  • Bannach O, Reinartz E, Henke F, Dreßen F, Oelschlegel A, Kaatz M, Groschup M H, Willbold D, Riesner D and Birkmann E 
    Analysis of prion protein aggregates in blood and brain from pre-clinical and clinical BSE cases 
    Vet Microbiol 166, 102-108 (2013) 
    http://dx.doi.org/10.1016/j.vetmic.2013.05.021  
  • Bannach O, Riesner D 
    Prions Overview 
    In: The Encyclopedia of Biological Chemistry. William J. Lennarz, M. Daniel Lane (eds.), Elsevier Inc. 3, 571-575 (2013) 
  • Luers, L, Bannach, O, Stöhr, J, Wördehoff, MM, Wolff M, Nagel-Steger, L, Riesner, D, Willbold, D, Birkmann E 
    Seeded Fibrillation as Molecular Basis of the Species Barrier in Human Prion Diseases 
    PloS ONE 8, e72623 (2013) 
  • Marbach, J; Zentis, P; Ellinger, P; Müller, H; Birkmann, E 
    Expression and characterization of fully posttranslational modified cellular prion protein in Pichia pastoris 
    Biol. Chem. 394, 1475-1483 (2013) 
  • Bannach O, Birkmann E, Reinartz E, Jaeger K-E, Langeveld JP, Rohwer RG, Gregory L, Terry LA, Willbold D, Riesner D 
    Detection of Prion Protein Particles in Blood Plasma of Scrapie Infected Sheep 
    PLoS ONE 7, e36620 (2012) 
    http://dx.doi.org/10.1371/journal.pone.0036620  
    full text open access  
  • Neudecker P, Robustelli P, Cavallli A, Walsh P, Lundstrom P, Zarrine-Afsar A, Sharpe S, Vendruscolo M, Kay LE 
    Structure of an intermediate state in protein folding and aggregation. 
    Science 336, 362-366 (2012) 
  • Stöhr J, Elfrink K, Weinmann N, Wille H, Willbold D, Birkmann E and Riesner D 
    In vitro conversion of the posttranslationally modified prion protein. 
    Biol. Chem. 392, 415-421 (2011) 
  • Luers L, Panza G, Henke F, Aygenim T, Weiß J, Willbold D, Birkmann E 
    Amyloid formation: Age-related mechanism in Creutzfeldt-Jakob disease? 
    Rejuvenation Res. 13, 214-216 (2010) 
  • Panza G, Dumpitak C, Birkmann E 
    Amyloid formation: Influence of the Maillard Reaction to Prion Protein Aggregation. 
    Rejuvenation Res. 13, 220-223 (2010) 
  • Panza G, Luers L, Stöhr J, Nagel-Steger L, Weiβ J, Riesner D, Willbold D, Birkmann E 
    Molecular interactions between prions as seeds and recombinant prion proteins as substrates resemble the biological interspecies barrier in vitro. 
    PLoS ONE 5, e14283 (2010) 
    http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0014283  
  • Mangels C, Frank AO, Ziegler J, Klingenstein R, Schweimer K, Willbold D, Korth C, Rösch P, Schwarzinger S 
    Binding of TCA to the prion protein: mechanism, implication for therapy, and application as probe for complex formation of bio-macromolecules. 
    J. Biomol. Struct. Dyn. 27, 163-170 (2009) 
  • Birkmann E & Riesner D 
    Prion infection – seeded fibrillization or more? 
    Prion 2, 67-72 (2008) 
  • Birkmann E, Henke F, Funke SA, Bannach O, Riesner D, Willbold D 
    A highly sensitive diagnsotic assay for aggregate-related diseases e.g. prion disease and Alzheimer's disease. 
    Rejuvenation Res. 11, 359-363 (2008) 
  • Elfrink K, Ollesch J, Stoehr J, Willbold D, Riesner D, Gerwert K 
    Structural changes of PrPc upon membrane anchoring. 
    Proc. Natl. Acad. Sci. 105, 10815-10819 (2008) 
  • Kaimann T, Metzger S, Kuhlmann K, Brandt B, Birkmann E, Höltje HD, Riesner D 
    Molecular model of an alpha-helical prion protein dimer and its monomeric subunits as derived from chemical cross-linking and molecular modeling calculations. 
    J.Mol.Biol. 376, 582-596 (2008) 
  • Müller H, Stitz L, Riesner D  
    Prion decontamination during the oleochemical process of fat hydrogenation. 
    Eur J Lipid Sci Technol 110, 392-399 (2008) 
    http://dx.doi.org/10.1002/ejlt.200700171  
  • Panza G, Stöhr J, Birkmann E, Riesner D, Willbold D, Baba O, Terashima T, Dumpitak C 
    Aggregation and amyloid fibril formation of the prion protein is accelerated in presence of glycogen. 
    Rejuvenation Res. 11, 365-369 (2008) 
  • Panza G, Stöhr J, Dumpitak C, Papathanassiou D, Weinmann N, Weiß J, Riesner D, Willbold D, Birkmann E 
    Spontaneous and BSE-prion-seeded amyloid formation of full length recombinant bovine Prion Protein. 
    Biochem. Biophys. Research Comm. 373, 493.497 (2008) 
  • Stöhr J, Weinmann N, Wille H, Kaimann T, Nagel-Steger L, Birkmann E, Panza G, Prusiner SB, Eigen M, Riesner D 
    Mechanisms of prion protein assembly into amyloid. 
    Proc. Natl. Acad. Sci. U S A 105, 2409-2414 (2008) 
    http://dx.doi.org/10.1073/pnas.0712036105  
  • Birkmann E, Henke F, Weinmann N, Dumpitak C, Groshup M, Funke SA, Willbold D, Riesner D, 
    Counting of single prion particles bound to a capture-antibody surface (surface-FIDA), 
    Vet. Microbiol. 123, 294-304 (2007) 
  • Elfrink K, Nagel-Steger L, Riesner D 
    Interaction of the cellular prion protein with raft-like lipid membranes. 
    Biol. Chem. 388, 79-90 (2007) 
    http://dx.doi.org/10.1515/BC.2007.010, 01/01/2007  
  • Müller H, Stitz L, Wille H, Prusiner SB, Riesner D 
    Influence of water, fat, and glycerol on the mechanism of thermal prion inactivation. 
    J Biol Chem 282, 35855-35867 (2007) 
    http://dx.doi.org/10.1074/jbc.M706883200  
  • Birkmann E, Schafer O, Weinmann N, Dumpitak C, Beekes M, Jackman R, Thorne L, Riesner D 
    Detection of prion particles in samples of BSE and scrapie by fluorescence correlation spectroscopy without proteinase K digestion. 
    Biol Chem. 387, 95-102 (2006) 
  • Riesner, D, Birkmann E, Dumpitak C, Elfrink K, Kellings K, Leffers K-W, Nagel-Steger L, Stöhr J 
    PrP-Fibrillen und Infektiosität 
    Nova Acta Leopoldina 347, 61-77 (2006) 
  • Leffers KW, Schell J, Jansen K, Lucassen R, Kaimann T, Nagel-Steger L, Tatzelt J, Riesner D 
    The structural transition of the prion protein into its pathogenic conformation is induced by unmasking hydrophobic sites. 
    J Mol Biol 344, 839-853 (2004) 
    http://dx.doi.org/10.1016/j.jmb.2004.09.071  
  • Riesner D 
    No molecular basis of prion diseases. 
    J Neurovirol. 8, Suppl. 2: 8-20 (2002) 
  • Appel T, Wolff M, von Rheinbaben F, Heinzel M, Riesner D 
    Heat stability of prion rods and recombinant prion protein in water, lipid and lipid-water mixtures. 
    J Gen Virol. 82, 465-473 (2001) 
  • Jansen K, Schafer O, Birkmann E, Post K, Serban H, Prusiner SB, Riesner D 
    Structural intermediates in the putative pathway from the cellular prion protein to the pathogenic form. 
    Biol Chem. 382, 683-691 (2001) 
  • Riesner D 
    No The prion theory: background and basic information. 
    Contrib Microbiol. 7, 7-20 (2001) 
  • Riesner D 
    Prions and their biophysical background  
    Biophys Chem 66, 259-268 (1997) 
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