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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).

Prion1

1982 veröffentlichte Stanley B. Pruisiner die Prion-Hypothese, welche besagt, dass der Erreger der Prionkrankheiten ausschließlich aus proteinösen Partikeln (Prionen) bestand. Der Hauptbestandteil der Prionen ist das Prion Protein in einer fehlgefalteten Struktur (PrPSc). Das Prion Protein ist ein körpereigenes 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.

weiterführende Links

  • Frenzel D, Glück JM, Brener O, Oesterhelt F, Nagel-Steger L, Willbold D
    Immobilization of homogeneous monomeric, oligomeric and fibrillar Aβ species for reliable SPR measurements
    PLoS ONE 9, e89490 (2014)
  • Grüning CS, Mirecka EA, Klein AN, Mandelkow E, Willbold D, Marino SF, Stoldt M, Hoyer W
    Alternative conformations of the tau repeat domain in complex with an engineered binding protein
    J. Biol. Chem. , (2014)
    http://dx.doi.org/10.1074/jbc.M114.560920
    http://www.jbc.org/content/early/2014/06/25/jbc.M114.560920.abstract
  • Mirecka EA, Shaykhalishahi H, Gauhar A, Akgül S, Lecher J, Willbold D, Stoldt M, Hoyer W
    Sequestration of a beta-hairpin for control of alpha-synuclein aggregation
    Angew. Chem. Int. Ed. 53, 4227-4230 (2014)
    http://dx.doi.org/10.1002/anie.201309001
    http://dx.doi.org/10.1002/ange.201309001
  • Olubiyi OO, Frenzel D, Bartnik D, Glück JM, Brener O, Nagel-Steger L, Funke SA, Willbold D, Strodel B
    Amyloid aggregation inhibitory mechanism of arginine-rich D-peptides
    Curr. Med. Chem. 21, 1448-1457 (2014)
  • Widera M, Klein NA, Cinar Y, Funke SA, Willbold D, Schaal H
    The D-amino acid peptide D3 reduces amyloid fibril boosted HIV-1 infectivity
    AIDS Res. Therapy 11, 1 (2014)
  • Dornieden S, Müller-Schiffmann A, Sticht H, Cinar Y, Wördehoff M, Korth C, Funke SA, Willbold D
    Characterization of a single-chain variable fragment recognizing a linear epitope of Aß: A biotechnical tool for studies on Alzheimer's disease?
    PLoS ONE 8, e59820 (2013)
  • Grüning CS, Klinker S, Wolff M, Schneider M, Toksöz K, Klein AN, Nagel-Steger L, Willbold D, Hoyer W
    The off-rate of monomers dissociating from amyloid-beta protofibrils
    J. Biol. Chem. 288, 37104-37111 (2013)
    http://www.jbc.org/lookup/doi/10.1074/jbc.M113.513432
  • van Groen T, Kadish I, Funke SA, Bartnik D, Willbold D
    Treatment with D3 removes amyloid deposits, reduces inflammation, and improves cognition in old AβPP/PS1 double transgenic mice.
    J Alzheimer's Dis. 34, 609-620 (2013)
    open access
  • Wang-Dietrich L, Funke SA, Kühbach K, Wang K, Besmehn A, Willbold S, Cinar Y, Bannach O, Birkmann E, Willbold D
    The Aβ oligomer count in CSF is a biomarker for Alzheimer?s disease.
    J. Alzheimers Dis. 34, 985-994 (2013)
  • Funke SA, Bartnik D, Glück JM, Pirkowska K, Wiesehan K, Weber U, Gulyas B, Halldin C, Pfeifer A, Spenger C, Muhs A, Willbold D
    Development of a small D-enantiomeric Alzheimer's amyloid-beta binding peptide ligand for future in vivo imaging applications.
    PLoS ONE 7, e41457 (2012)
  • Funke SA, Liu H, Sehl T, Bartnik D, Brener O, Nagel-Steger L, Wiesehan K, Willbold D
    Identification and characterization of an Aβ oligomer precipitating peptide that may be useful to explore gene therapeutic approaches to Alzheimer?s disease.
    Rejuv. Res. 15, 144-147 (2012)
  • Funke SA, Willbold D
    Peptides for Therapy and Diagnosis of Alzheimer?s Disease.
    Curr. Pharm. Design 18, 755-767 (2012)
  • Jahan M, Nag S, Krasikova R, Weber U, Muhs A, Pfeifer A, Spenger C, Willbold D, Gulyás B, Halldin C
    Fluorine-18 labeling of three novel d-peptides by conjugation with N-succinimidyl-4-[(18)F]fluorobenzoate and preliminary examination by postmortem whole-hemisphere human brain autoradiography.
    Nucl. Med. Biol. 392, 315-323 (2012)
  • Kroth H, Ansaloni A, Varisco Y, Jan A, Sreenivasachary N, Rezaei-Ghaleh N, Giriens V, Lohmann S, Pilar López-Deber M, Adolfsson O, Pihlgren M, Paganetti P, Froestl W, Nagel-Steger L, Willbold D, Schrader T, Zweckstetter M, Pfeifer A, Lashuel HA, Muhs A
    Discovery and structure activity relationship of small molecule inhibitors of toxic β-amyloid-42 fibril formation.
    J. Biol. Chem. 287, 34786-34800 (2012)
  • Mazargui H, Lévêque C, Bartnik D, Fantini J, Gouget T, Melone MA, Funke SA, Willbold D, Perrone L
    A synthetic amino acid substitution of Tyr10 in Aβ peptide sequence yields a dominant negative variant in amyloidogenesis.
    Aging Cell 11, 530-541 (2012)
  • 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)
  • Sun N, Funke SA, Willbold D
    A survey of peptides with effective therapeutic potential in Alzheimer?s disease rodent models or in human clinical studies.
    Mini. Rev. Med. Chem. 12, 388-398 (2012)
    full text open access
  • Sun N, Funke SA, Willbold D
    Mirror image phage display - Generating stable therapeutically and diagnostically active peptides with biotechnological means.
    J. Biotech. 161, 121-125 (2012)
    10.1016/j.jbiotec.2012.05.019
    full text
  • Sun N, Hartmann R, Lecher J, Stoldt M, Funke SA, Gremer L, Ludwig H-H, Demuth H-U, Kleinschmidt M, Willbold D
    Structural analysis of the pyroglutamate modified isoform of the Alzheimer's disease related beta-amyloid using NMR spectroscopy.
    J. Pept. Science 18, 691-695 (2012)
  • van Groen T, Kadish I, Funke A, Bartnik D, Willbold D
    Treatment with Aβ42 Binding d-Amino Acid Peptides Reduce Amyloid Deposition and Inflammation in APP/PS1 Double Transgenic Mice.
    Adv. Protein. Chem. Struct. Biol. 88, 133-152 (2012)
  • Funke SA
    Detection of Soluble Amyloid-β Oligomers and Insoluble High-Molecular-Weight Particles in CSF: Development of Methods with Potential for Diagnosis and Therapy Monitoring of Alzheimer's Disease.
    Int J Alzheimers Dis. 2011, 151645 (2011)
  • Funke SA, Willbold D
    Quantitation of Amyloid-β oligomers in human body fluids for Alzheimer?s disease early diagnosis or therapy monitoring.
    Alzheimer's diagnosis. Charles E. Ronson (Ed.), Hauppage, NY, USA (2011)
    Nova Science Publishers, ISBN 978-1-61209-846-3
  • Hickman DT, López-Deber MP, Ndao DM, Silva AB, Nand D, Pihlgren M, Giriens V, Madani R, St-Pierre A, Karastan H, Nagel-Steger L, Willbold D, Riesner D, Nicolau C, Baldus M, Pfeifer A, Muhs A
    Sequence-independent control of peptide conformation in liposomal vaccines for targeting protein misfolding diseases.
    J. Biol.Chem. 286, 13966-13976 (2011)
  • Hochdörffer K, März-Berberich J, Nagel-Steger L, Epple M, Meyer-Zaika W, Horn AH, Sticht H, Sinha S, Bitan G, Schrader T
    Rational Design of β-Sheet Ligands Against Aβ(42)-Induced Toxicity.
    J. Am. Chem. Soc. 133, 4348-4358 (2011)
  • van Groen T, Kadish I, Funke A and Willbold D
    Staining of Amyloid Beta (Abeta) Using (Immuno) Histochemical Techniques and Abeta42 Specific Peptides
    In: Neuroimaging for Clinicians - Combining Research and Practice. In Tech. Editor: Julio F. P. Peres; ISBN 978-953-307-450-4, Chapter 4 (2011)
    free download
  • Bartnik D, Funke SA, Andrei-Selmer L-C, Bacher M, Dodel R, Willbold D
    Differently selected D-enantiomeric peptides act on different Aß species.
    Rejuvenation Res. 13, 202-205 (2010)
  • Funke SA, van Groen T, Kadish I, Bartnik D, Nagel-Steger L, Brener O, Sehl T, Batra-Safferling R, Moriscot C, Schoehn G, Horn AHC, Müller-Schiffmann A, Korth C, Sticht H, Willbold D
    Oral Treatment with the D-Enantiomeric Peptide D3 Improves Pathology and Behavior of Alzheimer?s disease Transgenic Mice
    ACS Chem. Neurosci. 1, 639-648 (2010)
    http://dx.doi.org/10.1021/cn100057j
    Highlighted in: Chemical & Engineering News, 88(33), August 16, 2010
  • Funke SA, Wang L, Birkmann E, Willbold D
    Single particle detection system for Aß: Adaptation of surface-FIDA to laser scanning microscopy.
    Rejuvenation Res. 13, 206-209 (2010)
  • Liu HM, Funke SA, Willbold D
    Transport of Alzheimer's disease amyloid-ß peptide binding D-amino acid peptides across a blood-brain barrier in vitro model.
    Rejuvenation Res. 13, 210-213 (2010)
  • Luheshi LM, Hoyer W, de Barros TP, van Dijk-Härd I, Brorsson AC, Macao B, Persson C, Crowther DC, Lomas DA, Ståhl S, Dobson CM, Härd T
    Sequestration of the Abeta peptide prevents toxicity and promotes degradation in vivo
    PLoS Biol. 8, e1000334 (2010)
  • Müller-Schiffmann A, März-Berberich J, Andrjevna A, Rönicke R, Bartnik D, Brener O, Kutzsche J, Horn AHC, Hellmert M, Polkowska J, Gottmann K, Reymann K, Funke SA, Nagel-Steger L, Moriscot C, Schoehn G, Sticht H, Willbold D, Schrader T, Korth C
    Combining independent drug classes into superior, synergistically acting hybrid molecules.
    Angew. Chem. Int. Ed. Engl. 49, 8743-8746 (2010)
    http://dx.doi.org/10.1002/anie.201004437
  • Nagel-Steger L, Demeler B, Meyer-Zaika W, Hochdörffer K, Schrader T, Willbold D
    Modulation of aggregate size- and shape-distributions of the amyloid-beta peptide by a designed ß-sheet breaker.
    Eur. Biophys. J. 39, 415-422 (2010)
    http://dx.doi.org/10.1007/s00249-009-041
  • Demeler B, Brookes E, Nagel-Steger L
    Analysis of heterogeneity in molecular weight and shape by analytical ultracentrifugation using parallel distributed computing.
    Meth. Enzymol. 454, 87-113 (2009)
    http://dx.doi.org/10.1016/S0076-6879(08)03804-4
  • Funke SA, Birkmann E, Willbold D
    Detection of Amyloid-β aggregates in body fluids: A suitable method for early diagnosis of Alzheimer's diesease?
    Curr. Alzheimer Res. 6, 285-289 (2009)
  • Funke SA, Willbold D
    Mirror image phage display - a method to generate D-peptide ligands for use in diagnostic or therapeutical applications?
    Mol. BioSyst. 5, 783-786 (2009)
  • Görtz P, Opatz J, Siebler M, Funke SA, Willbold D, Lange-Asschenfeldt C
    Transient reduction of spontaneous neuronal network activity by sublethal amyloid beta (1-42) peptide concentrations.
    J. Neural Transmission 116, 351-355 (2009)
  • Schlenzig D, Manhart S, Cinar Y, Willbold D, Funke SA, Kleinschmidt M, Hause G, Schilling S, Demuth H-U
    Pyroglutamate formation influences solubility and amyloidenicity of amyloid peptides. A driving force in different neurodegenerative disorders?
    Biochemistry 48, 7072-7078 (2009)
  • van Groen T, Kadish I, Wiesehan K, Funke, SA, Willbold D
    In vitro and in vivo staining characteristics of small, fluorescent, Aß42 binding D-enantiomeric peptides in transgenic AD mouse models.
    ChemMedChem 4, 276-282 (2009)
  • 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)
  • Funke SA, Birkmann E, Henke F, Görtz P, Lange-Asschenfeldt C, Riesner D, Willbold D
    An ultra sensitive assay for early diagnosis of Alzheimer's disease.
    Rejuvenation Res. 11, 315-318 (2008)
  • Nagel-Steger L, Demeler B, Hochdörfer K, Schrader T, Willbold D
    Modulation of aggregate size and shape distributions of amyloid-ß peptide solutions by a designed ß-sheet breaker.
    NIC Workshop 2008 (From Computational Biophysics to Systems Biology; CBSB08) Vol. 40, (2008)
    http://www.fz-juelich.de/nic-series/volume40/nagel_steger.pdf
  • van Groen T, Wiesehan K, Funke SA, Kadish I, Nagel-Steger L, Willbold D
    Reduction of Alzheimer's disease amyloid plaque load in transgenic mice by D3, a D-enantiomeric peptide identified by mirror image phage display.
    ChemMedChem 3, 1848-1852 (2008)
    http://dx.doi.org/10.1002/cmdc.200800273
    [This article was evaluated by the faculty of 1000 Biology as a "must read"]
  • Wiesehan K, Stöhr J, Nagel-Steger K, van Groen T, Riesner D and Willbold D
    Inhibition of cytotoxicity and fibril formation by a D-amino acid peptide that specifically binds to Alzheimer's disease amyloid peptide
    Prot. Eng. Des. Sel. 21, 241-246 (2008)
    http://dx.doi.org/10.1093/protein/gzm054
  • Funke SA, Birkmann E, Henke F, Görtz P, Lange-Asschenfeldt C, Riesner D, Willbold D,
    Single particle detection of amyloid-ß aggregates associated with Alzheimer's disease.
    Biochem. Biophys. Res. Comm. 364, 902-907 (2007)
  • Muhs A, Hickmann DT, Pihlgren M, Chuard N, Giriens V, Meerschman C, van der Auwera I, van Leuven F, Sugawara M, Weingertner MC, Bechinger B, Greferath R, Kolonko N, Nagel-Steger L, Riesner D, Brady RO, Pfeifer A, Nicolau C
    Liposomal vaccines with conformation-specific amyloid peptide antigens define immune response and efficacy in APP transgenic mice
    Proc. Natl. Acad. Sci. 104, 9810-9815 (2007)
    http://dx.doi.org/10.1073/pnas.0703137104
  • Nagel-Steger L, Demeler B, Willbold D
    Aggregate size and shape distributions in amyloid-ß peptide solutions. Aggregate Size and Shape Distributions in Amyloid-beta Peptide Solutions.
    NIC Workshop (From Computational Biophysics to Systems Biology; CBSB07) Vol. 36, (2007)
    http://www.fz-juelich.de/nic-series/volume36/nagel-steger.pdf
  • Wiesehan K, Funke SA, Fries M, Willbold D
    Purification of recombinantly expressed and cytotoxic human amyloid-beta peptide.
    J. Chrom. B 856, 229-233 (2007)
  • Wiesehan K, Buder K, Linke RP, Patt S, Stoldt M, Unger E, Schmitt B, Bucci E and Willbold D
    Selection of D-amino-acid peptides that bind to Alzheimer's disease amyloid peptide Abeta(1-42) by mirror image phage display.
    ChemBioChem 4, 748-753 (2003)
  • Wiesehan K, Willbold D
    Mirror image phage display: Aiming at the mirror.
    ChemBioChem 4, 811-815 (2003)
  • Willbold D & Wiesehan K
    Peptid zur Diagnose und Therapie der Alzheimer-Demenz National: DE 10117281A1, international: PCT/EP02/03862
    , (2001)

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