Cell Biology of Neurodegeneration
Prof. Dr. Dieter Edbauer
Group Leader
Feodor-Lynen-Str. 17
81377 München

dieter.edbauer@dzne.de
 +49 89 440046-510

Areas of investigation/research focus

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal neurodegenerative diseases with overlapping genetics and pathology. The most common cause is expansion of a (GGGGCC)n repeat in the first intron of the gene C9orf72. We discovered that the repeat region is translated in all reading frames into aggregating dipeptide-repeat (DPR) proteins (poly-GA, -GP, -GR, -PA and -PR) despite its intronic localization and lack of an ATG start codon (Mori&Weng et al., Science 2013). Funded by the ERC, the NOMIS foundation and the SyNergy excellence cluster (DFG), we are now analyzing the role of DPR proteins in pathogenesis from the ultrastructural to patient level in order to inhibit DPR synthesis and/or toxicity and thus prevent or treat C9orf72 ALS/FTD. Our cellular models show that DPR aggregates sequester key cellular proteins leading to toxicity (May et al., Acta Neuropathol 2014). The hydrophobic DPR proteins poly-GA, -GP and -PA are transmitted between cells (Zhou et al., EMBO Mol Med 2017). Since antibodies inhibit poly-GA uptake and aggregation in vitro, we are now testing immunotherapy in our mouse models. Using immunoassays, we detected poly-GP in the CSF of C9orf72 ALS and FTD patients (Lehmer et al., EMBO Mol Med 2017). Surprisingly, poly-GP levels are similar in presymptomatic and symptomatic C9orf72 carriers, indicating that DPR proteins play an early role in pathogenesis and may trigger TDP-43 pathology and neurodegeneration in a cascade-like mechanism.

 more Infos

We are dissecting C9orf72 pathogenesis further using primary neuron culture, mouse models (with B. Wefers, DZNE Munich), proteomics (with F. Meißner and M. Mann, MPI Martinsried) and cryo-electron tomography (with R. Fernandez-Busnadiego and W. Baumeister, MPI Martinsried). Whenever possible, we use human brain tissue to confirm our in vitro in patients (with T. Arzberger, DZNE Munich).  Using cellular assays, we aim to understand the mechanisms of the unusual translation of the expanded C9orf72 repeat to develop inhibitors for future therapy.

The current data on C9orf72 pathogenesis highlights the role of RNA-metabolism and protein degradation. Importantly, these pathways are also affected by pathogenic mutations in several other known ALS/FTD-causing genes, but it is unclear how any of these mutations trigger the stereotypic TDP-43 pathology found in ~90% of all ALS cases.  Therefore, we are also studying other confirmed and suspected ALS/FTD-causing mutations hoping to identify shared molecular mechanisms that lead to TDP-43 pathology, and ultimately neurodegeneration and disease. For example, we recently found that TDP-43 regulates the trafficking of recycling endosomes and subsequently affects neurotrophic signaling (Schwenk et al., EMBO J 2016).

Key Publications

Martin H. Schludi, Lore Becker, Lillian Garrett, Tania F. Gendron, Qihui Zhou, Franziska Schreiber, Bastian Popper, Leda Dimou, Tim M. Strom, Juliane Winkelmann, Anne von Thaden, Kristin Rentzsch, Stephanie May, Meike Michaelsen, Benjamin M. Schwenk, Jing Tan, Benedikt Schoser, Marianne Dieterich, Leonard Petrucelli, Sabine M. Hölter, Wolfgang Wurst, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabe de Angelis, Thomas Klopstock, Thomas Arzberger, Dieter Edbauer. Spinal poly-GA inclusions in a C9orf72 mouse model trigger motor deficits and inflammation without neuron loss. Acta Neuropathologica. 2017 Jul 31; 134:241-254. doi: 10.1007/s00401-017-1711-0
Stephanie May, Daniel Hornburg, Martin H. Schludi, Thomas Arzberger, Kristin Rentzsch, Benjamin M. Schwenk, Friedrich A. Grässer, Kohji Mori, Elisabeth Kremmer, Julia Banzhaf-Strathmann, Matthias Mann, Felix Meissner, Dieter Edbauer. C9orf72 FTLD/ALS-associated Gly-Ala dipeptide repeat proteins cause neuronal toxicity and Unc119 sequestration. Acta Neuropathologica. 2013 Dec 31; 128:485-503. doi: 10.1007/s00401-014-1329-4
Kohji Mori, Shih-Ming Weng, Thomas Arzberger, Stephanie May, Kristin Rentzsch, Elisabeth Kremmer, Bettina Schmid, Hans A. Kretzschmar, Marc Cruts, Christine Van Broeckhoven, Christian Haass, Dieter Edbauer. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science. 2013 Mar 14; 339:1335-1338. doi: 10.1126/science.1232927
Edbauer D, Neilson JR, Foster KA, Wang CF, Seeburg DP, Batterton MN, Tada T, Dolan BM, Sharp PA, Sheng M. Regulation of synaptic structure and function by FMRP-associated microRNAs miR-125b and miR-132. Neuron. 2010 Feb 11; 65:373-84. doi: 10.1016/j.neuron.2010.01.005
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