Susanne Wegmann
Protein Actions in Neurodegeneration
Susanne Wegmann, PhD, Dipl.-Ing.
Group Leader
Charitéplatz 1
intern: Virchowweg 6
10117  Berlin
 +49 30 450-539834

Research areas/focus

Proteins are the ‘work horses’ of cells and enable almost all cellular functions, from genome organization over signaling cascades up to the mechanical support of cellular structures and transport of molecules. Neurons are especially polarized non-dividing cells with extreme extensions and diverse microenvironments, which asks for robustly regulated and highly specialized protein actions and functions in different compartments and situations. In neurodegenerative diseases and during aging, protein actions can change, and loss of function, misfunctions, and aggregation of proteins are commonly observed.

In our group we use a wide spectrum of experimental methodologies and techniques – from biophysical and biochemical techniques, to cell culture and animal models,  and to postmortem human tissue - to discover the actions that proteins take during their normal function and during misfunction in the diseased brain. Thereby we currently focus on (but are not exclusive about it) the intrinsically unfolded neuronal microtubule-associated tau protein, which aggregates in multiple different neurodegenerative diseases. But tau also seems to harbor a variety of other functions in the cell that yet need to be explored. Identifying such unusual functions of tau (and other proteins) in the brain provides the opportunity to explain toxicity effects and enables the development of novel therapeutic approaches.

 more Infos

The following research areas are currently addressed in our group:

1. Liquid phase separation and condensation of tau and other proteins in neurodegeneration.

Transient stress granule formation in cells is driven by liquid-liquid phase separation (LLPS) of RNA-binding proteins, and in diseases conditions can lead to protein aggregation, e.g. in case of FUS and TDP-43 in ALS. We and others showed that also tau can undergo LLPS, which can initiate aggregation as well (Wegmann et al, EMBO J 2018). We want to determine the role of tau LLPS in Alzheimer’s disease and tauopathies.

2. Tau interactions with neuronal multi-protein assemblies.

In AD and tauopathies, the axonal tau protein becomes (hyper)phosphorylated and occurs in the cell soma, where it then can interact aberrantly with intracellular molecules and structures, e.g. the nucleus and proteins in the nuclear membrane. We showed that tau can interact with protein entities (nucleoporins) of the nuclear pore complex and inhibit essential pore functions in nucleocytoplasmic transport (Eftekharzadeh et al, Neuron 2018). We are now interested in the molecular mechanisms and cellular consequences of these interactions.

3. Selective vulnerability of brain regions effected in disease. 

The cognitive decline of AD patients correlates with the progression of tau protein aggregation in the  brain. In sporadic AD, the pathological hallmark of tau aggregation, Neurofibrillary tangles (NFTs), follows a hierarchical pattern: trans-synaptic propagation of tau leads to pathology spread from the entorhinal cortex to the hippocampus, and further through limbic system to and frontal and other cortical areas. We want to know, to which extend selective vulnerability of brain regions is involved in the disease etiology of neurodegenerative diseases.

Key Publications

Bahareh Eftekharzadeh, J. Gavin Daigle, Larisa E. Kapinos, Alyssa Coyne, Julia Schiantarelli, Yari Carlomagno, Casey Cook, Sean J. Miller, Simon Dujardin, Ana S. Amaral, Jonathan C. Grima, Rachel E. Bennett, Katharina Tepper, Michael DeTure, Charles R. Vanderburgh, Bianca T. Corjuc, Sarah L. DeVos, Jose Antonio Gonzalez, Jeannie Chew, Svetlana Vidensky, Fred H. Gage, Jerome Mertens, Juan Troncoso, Eckhard Mandelkow, Xavier Salvatella, Roderick Y.H. Lim, Leonard Petrucelli, Susanne Wegmann, Jeffrey D. Rothstein, Bradley T. Hyman. Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer's Disease. Neuron. 2018 Sep 04; 99:925-940.e7. doi: 10.1016/j.neuron.2018.07.039
Susanne Wegmann, Bahareh Eftekharzadeh, Katharina Tepper, Katarzyna M Zoltowska, Rachel E Bennett, Simon Dujardin, Pawel R Laskowski, Danny MacKenzie, Tarun Kamath, Caitlin Commins, Charles Vanderburg, Allyson D Roe, Zhanyun Fan, Amandine M Molliex, Amayra Hernandez-Vega, Daniel Muller, Anthony A Hyman, Eckhard Mandelkow, J Paul Taylor, Bradley T Hyman. Tau protein liquid–liquid phase separation can initiate tau aggregation. EMBO Journal. 2018 Apr 02; 37 doi: 10.15252/embj.201798049
Wegmann S, Maury EA, Kirk MJ, Saqran L, Roe A, DeVos SL, Nicholls S, Fan Z, Takeda S, Cagsal-Getkin O, William CM, Spires-Jones TL, Pitstick R, Carlson GA, Pooler AM, Hyman BT. Removing endogenous tau does not prevent tau propagation yet reduces its neurotoxicity. EMBO J. 2015 Dec 14; 34:3028-41. doi: 10.15252/embj.201592748
Kuchibhotla KV, Wegmann S, Kopeikina KJ, Hawkes J, Rudinskiy N, Andermann ML, Spires-Jones TL, Bacskai BJ, Hyman BT. Neurofibrillary tangle-bearing neurons are functionally integrated in cortical circuits in vivo. Proc Natl Acad Sci U S A. 2014 Jan 07; 111:510-4. doi: 10.1073/pnas.1318807111
Wegmann S, Medalsy ID, Mandelkow E, Müller DJ. The fuzzy coat of pathological human Tau fibrils is a two-layered polyelectrolyte brush. Proc Natl Acad Sci U S A. 2013 Jan 22; 110:E313-21. doi: 10.1073/pnas.1212100110


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