Protein Misfolding Diseases

More than 300,000 new cases of amyloidoses are recorded in Germany every year. The diseases are caused by abnormally modified proteins being deposited in the body, usually in intercellular spaces. These insoluble protein fibrils, referred to as amyloids, damage not only the nervous system but also internal organs such as the heart, liver, kidneys, spleen or gastrointestinal tract and, in severe cases, also lead to their loss of function.

The Protein Misfolding Diseases unit carries out research into the impact of protein post-translational modifications and their influence on the emergence and prevention of amyloid diseases. To be able to detect pathogenic modifications using immunological assays, amyloid proteins are first expressed, purified and made to aggregate in vitro. Monoclonal antibodies are then produced and tested as therapeutic agents. The aim here is to develop personalized treatments in the form of antibodies.

  • Production (cloning) of expression vectors
  • Heterologous expression of proteins in E. coli, yeast, and insect and mammalian cells
  • Column chromatographic purification of proteins on an analytical and semi-preparative scale
  • Spectroscopic analysis of protein structures and aggregation kinetics in vitro (CD and fluorescence spectroscopy)
  • Development of enzyme assays
  • Structure-based optimization of antibodies (protein engineering)
  • Electron microscopy, dynamic light scattering or small-angle X-ray scattering (together with cooperation partners)

  • Cynis H, Frost JL, Crehan H, Lemere CA. Immunotherapy targeting pyroglutamate-3 Aβ: prospects and challenges. Mol Neurodegener. 2016 Jun 30;11(1):48. doi: 10.1186/s13024-016-0115-2.
  • Hielscher-Michael S, Griehl C, Buchholz M, Demuth HU, Arnold N, Wessjohann LA. Natural Products from Microalgae with Potential against Alzheimer's Disease: Sulfolipids Are Potent Glutaminyl Cyclase Inhibitors. Mar Drugs. 2016 Nov 2;14(11). pii: E203.
  • Wulff M, Baumann M, Thümmler A, Yadav JK, Heinrich L, Knüpfer U, Schlenzig D, Schierhorn A, Rahfeld JU, Horn U, Balbach J, Demuth HU, Fändrich M. Enhanced Fibril Fragmentation of N-Terminally Truncated and Pyroglutamyl-Modified Aβ Peptides. Angew Chem Int Ed Engl. 2016 Apr 11;55(16):5081-4. doi: 10.1002/anie.201511099. Epub 2016 Mar 11.
  • Cynis H, Funkelstein L, Toneff T, Mosier C, Ziegler M, Koch B, Demuth HU, Hook V. Pyroglutamate-amyloid-β and glutaminyl cyclase are colocalized with amyloid-β in secretory vesicles and undergo activity-dependent, regulated secretion. Neurodegener Dis. 2014;14(2):85-97. doi: 10.1159/000358430. Epub 2014 Jun 18.
  • Schlenzig D, Rönicke R, Cynis H, Ludwig HH, Scheel E, Reymann K, Saido T, Hause G, Schilling S, Demuth HU. N-Terminal pyroglutamate formation of Aβ38 and Aβ40 enforces oligomer formation and potency to disrupt hippocampal long-term potentiation. J Neurochem. 2012 Jun;121(5):774-84. doi: 10.1111/j.1471-4159.2012.07707.x. Epub 2012 Mar 28.
  • Schlenzig D, Manhart S, Cinar Y, Kleinschmidt M, Hause G, Willbold D, Funke SA, Schilling S, Demuth HU. Pyroglutamate formation influences solubility and amyloidogenicity of amyloid peptides. Biochemistry. 2009 Jul 28;48(29):7072-8. doi: 10.1021/bi900818a.
  • Schilling S, Zeitschel U, Hoffmann T, Heiser U, Francke M, Kehlen A, Holzer M, Hutter-Paier B, Prokesch M, Windisch M, Jagla W, Schlenzig D, Lindner C, Rudolph T, Reuter G, Cynis H, Montag D, Demuth HU, Rossner S. Glutaminyl cyclase inhibition attenuates pyroglutamate Abeta and Alzheimer's disease-like pathology. Nat Med. 2008 Oct;14(10):1106-11. doi: 10.1038/nm.1872. Epub 2008 Sep 28.
  • Buchholz M, Heiser U, Schilling S, Niestroj AJ, Zunkel K, Demuth HU. The first potent inhibitors for human glutaminyl cyclase: synthesis and structure-activity relationship. J Med Chem. 2006 Jan 26;49(2):664-77.
  • Cynis H, Schilling S, Bodnár M, Hoffmann T, Heiser U, Saido TC, Demuth HU. Inhibition of glutaminyl cyclase alters pyroglutamate formation in mammalian cells. Biochim Biophys Acta. 2006 Oct;1764(10):1618-25. Epub 2006 Aug 16.
  • Schilling S, Lauber T, Schaupp M, Manhart S, Scheel E, Böhm G, Demuth HU. On the seeding and oligomerization of pGlu-amyloid peptides (in vitro). Biochemistry. 2006 Oct 17;45(41):12393-9.