25-30 August 2019
Henry Ford Building
Europe/Berlin timezone

Modulation of aggregating proteins studied by NMR and beyond in neuro- and cellular degeneration

27 Aug 2019, 16:50
25m
Max Kade Auditorium (Henry Ford Building)

Max Kade Auditorium

Henry Ford Building

Invited talk Biological applications NMR in Drug Design

Speaker

Prof. Christian Griesinger (MPIbpc)

Description

In Parkinson’s disease (PD), a-Synuclein aggregates to Lewy bodies, which are connected to neuronal dysfunction and death, similar to Abeta and tau in Alzheimer’s (AD), prion protein in Creutzfeldt Jacob and IAPP in Type II diabetes mellitus (T2DM). Using structural biology derived predictions (1), a-Synuclein is shown to form non-toxic intrinsically disordered monomers and non-toxic fibrils, while immediate toxicity is exerted by oligomers (2). Prevention of formation of these toxic oligomers by small molecules, specifically anle138b, observed in vitro and in vivo (3) using ultracentrifugation or superresolution imaging, specifically anle138b, leads to neuroprotection and restoration of functionality of the neurons in all mentioned diseases, specifically in PD (3), MSA (4), AD based on tau (5) or Abeta42 overexpression (6) and T2DM (7). Biophysical characterization of anle138b with target proteins will be discussed (5,8) in solution and in membranes with NMR spectroscopy.

1) Bertoncini, CW; et al. PNAS, 102 (5): 1430-1435
2) Karpinar, DP; et al. Embo Journal, 28 (20): 3256-3268
3) Wagner, J; et al. Acta Neuropathol. 125, 795-813 (2013); Levin, J; et al. Act. Neuropath. 127, 779-780 (2014); Giese, A; Bertsch, U; Kretzschmar, H; Habeck, M; Hirschberger, T; Tavan, P; Griesinger, C; Leonov, A;, Ryazanov, S; Weber, P; Geissen, M; Groschup, MH; Wagner, J. (2010) WO/2010/000372; A. Giese, F. Schmidt, C. Griesinger, A. Leonov, S. Ryzanov: WO2017/102893; Wegrzynowicz M et al. Acta Neuropathol.https://doi.org/10.1007/s00401-019-02023-x (2019)
4) Heras-Garvin, A. et al. Movement Disorders in press
5) Wagner, J. et al. Act. Neuropath.130, 619-631 (2015);
6) Martinez Hernandez, A; et al. EMBO Mol. Med. 10, 32-47 (2018)
7) J. Hoppener et al. “Glucose and HbA1c normalization and insulin sensibilization in a HIAPP overexpression model in T2DM” in preparation
8) Deeg, A.A. et al. Biochim. Biophys. Act. 1850 (9), 1884-1890 (2015); Reiner, A.M. et al. Biochim. Biophys. Acta Gen. Subj. 1862, 800-807 (2018)

Primary authors

Mr Sergey Ryazanov (MPIbpc) Mr Leif Antonschmidt (MPIbpc) Dr Riza Dervisoglu (MPIbpc) Mr Kris Runge (MPIbpc) Dr Stefan Becker (MPIbpc) Dr Andrei Leonov (MPIbpc) Dr Loren B Andreas (MPIbpc) Dr Armin Giese (MODAG) Prof. Christian Griesinger (MPIbpc)

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