Prof. Dr. Funke has worked for about ten years on therapy and diagnostics of neurodegenerative diseases, like AD. Her major research focus is the investigation of protein ligand interactions by various methods, e.g., fluorescence microscopy, SPR, and a variety of other biochemical and biophysical methods. In the lab of Prof. Dr. Dieter Willbold (Forschungszentrum Jülich), she investigated Aβ binding peptides for therapy and diagnosis of AD. Additionally, Funke is interested in the field of biomarker research and developed a new technique for the detection of Aβ oligomers in cerebrospinal fluid.
Peptides for therapy and diagnosis of Alzheimer’s disease
A variety of neurodegenerative disorders, including Alzheimer’s disease, are associated with neurofibrillary tangles composed of the tau protein, as well as toxic tau oligomers, which can spread from cell to cell by a prion-like mechanism. Inhibitors of pathological tau aggregation might be useful for the development of therapeutics. Employing mirror-image phage display with large peptide libraries (> 1 billion different peptides), we identify tau binding peptides consisting of D-enantiomeric amino acids. D-enantiomeric peptides are extremely protease stable and not or less immunogenic than L-peptides, and the suitability of D-peptides for in vivo applications have already been demonstrated. Those D-enantiomeric peptides, which bind to aggregating Tau variants, as well as to full lengths Tau fibrils, modulate the aggregation thereof. They might be an interesting starting point for therapy development.
Dammers C, Yolcu D, Kukuk L, Willbold D, Pickhardt M, Mandelkow E, Horn AHC, Sticht H, Malhis M, Will N, Schuster J, Funke SA. Selection and Characterization of Tau binding D-enantiomeric Peptides with Potential for Therapy of Alzheimer Disease. PLoS One. 2016 Dec 22;11(12):e0167432. doi: 10.1371/journal.pone.0167432.
Specific Peptides to prevent the bacteria-host interaction and listeriosis
Listeria monocytogenes is a pathogenic bacterium responsible for foodborne infections and listeriosis, a disease with a high mortality rate. L. monocytogenes is able to enter, survive and multiply in different cells. Entry into human epithelial cells requires expression of Internalin A (InlA), a bacterial surface protein, which recognizes and binds E-cadherin, a surface protein of human cells. This interaction induces the internalization into host cells and triggers the infection. In spite of treating with antibiotics, 20 – 30 % of clinical infections result in death. High-risk groups, such as newborns, pregnant women and immunocompromised patients, are especially affected. The current commercially available tests for listeria are mostly culture techniques which are labour and time intensive. To enhance the detection and identification of the pathogen, more rapid methods are needed to meet current demands for food safety testing.
Using a technique called phage display, we develop specific peptides that bind to the surface protein Internalin A of the bacteria. Labeling of these peptides with a fluorophore can facilitate the detection of listeria in human cells or in food samples. Additionally, these selected InlA binding peptides might be used to inhibit the interaction between Internalin A and human E-Cadherin and therefore, to avoid the entry of the pathogen into host cells
Dammers C, Yolcu D, Kukuk L, Willbold D, Pickhardt M, Mandelkow E, Horn AHC, Sticht H, Malhis M, Will N, Schuster J, Funke SA (2016) Selection and Characterization of Tau binding D-enantiomeric Peptides with Potential for Therapy of Alzheimer Disease. PLoS One. 2016 Dec 22;11(12):e0167432. doi: 10.1371/journal.pone.0167432.
Brener O, Dunkelmann D, Gremer L, van Groen T, Mirecka E, Kadish I, Willuweit A, Kutzsche J, Jürgens D, Rudolph S, Tusche M, Bongen P, Pietruszka J, Oesterhelt F, Langen K-J, Demuth H-U, Janssen A, Hoyer W, Funke SA, Nagel-Steger L, Willbold D (2015) QIAD assay for quantitating a compound’s efficacy in elimination of toxic Aβ oligomers. Sci Rep 5, 13222.
van Groen T, Kadish I, Funke SA, Bartnik D, Willbold D (2013) Treatment with D3 Removes Amyloid Deposits, Reduces Inflammation, and Improves Cognition in Old AβPP/PS1 Double Transgenic Mice. J Alzheimers Dis 34, 609-20.
Wang-Dietrich L, Funke SA, Kühbach K, Wang K, Besmehn A, Willbold S, Cinar Y, Bannach O, Birkmann E, Willbold D (2013) The Amyloid-β Oligomer Count in Cerebrospinal Fluid is a Biomarker for Alzheimer’s Disease. J. Alzheimers Dis., 34(4):985-94.
Funke SA, Bartnik D, Glück JM, Piorkowska K, Wiesehan K, Weber U, Gulyas B, Halldin C, Pfeifer A, Spenger C, Muhs A, Willbold D (2012) Development of a small D-enantiomeric Alzheimer’s amy-loid-β binding peptide ligand for future in vivo imaging applications. Plos One e41457.
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 (2010) Oral Treatment with the D-Enantiomeric Peptide D3 Improves Pathology and Behavior of Alzheimer’s disease Transgenic Mice. ACS Chem Neuroscience 1, 639-648.