|Name||Prof. Dr. Eva-Maria Mandelkow|
|since 1986||Max-Planck-Workgroup for Structural Molecularbiology, Hamburg (Groupleader, C3)|
|1976-1985||Max-Planck-Institute for medical research, Heidelberg (Scientic)|
|1973||Dr. in Biochemistry at the Max-Planck-Inst. for med. research, Heidelberg|
|1974-1975||Brandeis University, Waltham, Mass. (Postdoctorate)|
The Alzheimer disease is characterized by abnormal accumulations of proteins in the brain, the "amyloid plaques" and the "neurofibrillary tangles". They occur in brain regions that are important for learning and memory - this explains the cognitive deficits in Alzheimer disease.
The research in our lab focusses on the protein "Tau" which causes the formation of neurofibrillary tangles. We investigate the normal functions of Tau in nerve cells and the malfunctions related to disease. Tau proteins serve normally as stabilizers or "ties" for the microtubule "tracks" which are res- ponsible for transport of material up and down the long axonal extensions of neurons (for example cell organelles, synaptic vesicles, protein and RNA complexes).
These "cargoes" are pulled by "motor proteins" along the microtubules. The strength of Tau-microtubule binding is regulated by biochemical signals, such as phosphorylation. In Alzheimer disease the signal- ling mechanisms appear to be perturbed so that Tau detaches from the microtubules, the microtubule tracks fall apart and the transport system breaks down. At the same time the detached Tau protein be- gins to accumulate into "paired helical filaments" which then assemble into the neurofibrillary tangles that obstruct the interior space of the cells.
We are studying the signalling pathways of Tau, the responsible enzymes (protein kinases), and the consequences for transport within cells and for Tau protein aggregation. One approach is to synthesize the Tau proteins in bacteria in recombinant form, which allows specific modifications of their properties. We also introduce Tau into neuronal cells or into "transgenic" mice which serve as models for the toxicity of Tau in Alzheimer disease. We observe the formation of the anomalous paired helical filaments of Tau by biophysical methods and electron microscopy, and we can visualize the movement and distribution of Tau and cell organelles in real time by confocal fluorescence microscopy (see figure). One of the major goals is to identify substances which can correct the pathological behavior of Tau and thus allow the sur- vival of the nerve cells.
With these methods we characterized several protein kinases which can transform Tau protein into a state of pathological phosphorylation, notably the kinase family MARK which can detach Tau from micro- tubules. We showed that Tau can inhibit axonal transport by blocking the attachment of motor proteins to microtubules (see movie, blue axon). We developed several neuronal cell models and mouse models where the expression of Tau can be switched on and off, so that one can observe the toxic effects of Tau expression, phosphorylation, and aggregation separately.
By screening a library of 200,000 chemical compounds we have discovered a number of substances which are capable of preventing the aggre- gation of Tau protein. These substances are currently modi- fied and investigated in order to understand their mode of action in cells. The long-term goal is to de- velop strategies for prevention or therapy of Alz- heimer disease.
Figure legend: The movie shows nerve cells in culture with their growing cell processes (axons), as seen by confocal light microscopy. The red particles are mitochondria, the "power stations" of cells that generate chemical energy. The mitochondria move up and down the axons, pulled by motor proteins a- long microtubules (not visible here). One single axon expresses Tau protein labeled with a blue fluo- rescent marker (CFP). In this cell the movement of mitochondria is severely impaired.
For further information see: www.mpasmb-hamburg.mpg.de
Mandelkow, E.-M., Thies, E., Trinczek, B., Biernat, B., Mandelkow, E. (2004). MARK/PAR1 kinase is a regulator of microtubule-dependent transport in axons. J. Cell Biol. 167, 99-110.
Matenia, D., Griesshaber, B., Li, X-Y., Thiessen, A., Johne, C., Jiao, J., Mandelkow, E., Mandelkow, E.-M. (2005). PAK5 kinase is an inhibitor of MARK/Par-1 which leads to stable microtubules and dynamic actin. Mol. Biol. Cell 16, 4410-4422.
Khlistunova, I., Biernat, J., Wang, Y.-P., Pickhardt, M., von Bergen, M., Gazova, Z., Mandelkow, E., Mandelkow, E.-M. (2006). Inducible expression of tau in cell models of Alzheimer's disease: Aggregation is toxic to cells but can be rescued by inhibitor drugs. J. Biol. Chem. 281, 1205-1214..
Goldsbury, C., Mocanu, M., Thies, E., Kaether, C., Haass, C., Keller, P. Biernat, J., Mandelkow, E., Mandelkow, E.-M. (2006). Inhibition of APP trafficking by tau protein does not increase the generation of amyloid-beta. Traffic 7, 873-888.
Thies, E., Mandelkow, E.-M. (2007). Missorting of tau in neurons causes degeneration of synapses that can be rescued by MARK2/Par-1. J. Neurosci. 27, 2896-2907.
Eckermann, K., Mocanu, M., Khlistunova, I., Biernat, J, Nissen, A., Hofmann, A., Schönig, K., Bujard, H., Haemisch, A., Mandelkow, E., Zhou, L., Rune, G., Mandelkow, E.-M. (2007). The beta-propensity of Tau determines aggregation and synaptic loss in inducible mouse models of Alzheimer tauopathy. J. Biol. Chem. 282, 31755-31765
Wang, Y.P., Biernat, J., Pickhardt, M., Mandelkow, E., Mandelkow, E.-M. (2007). Stepwise proteolysis liberates tau fragments that nucleate the Alzheimer-like aggregation of full-length tau in a neuronal cell model. Proc. Natl. Acad. Sci. U.S.A. 104, 10252-10257.
Timm, T., Balusamy, K., Biernat, J., Mandelkow, E., Mandelkow, E.-M. (2008). Inhibition of MARK/Par-1 signalling pathway by GSK3b. J. Biol. Chem. 283, 18873-18882.
Johne, C., Matenia, D., Li, X. Y., Timm, T., Balusamy, K., Mandelkow, E.-M. (2008). Spred1 and TESK1 - two new interaction partners of the kinase MARKK/TAO1 that mediate crosstalk between the microtubule and actin cytoskeleton. Mol. Biol. Cell 19, 1391-1403.
Mocanu, M., Nissen, A. Eckermann, K., Khlistunova, I., Biernat, J, Drexler, D., Petrova, O., Schönig, K., Bujard, H., Mandelkow, E., Zhou, L., Rune, G., Mandelkow, E.-M. (2008). The potential for beta structure in the repeat domain of Tau protein determines aggregation, synaptic decay, neuronal loss, and co-assembly with endogenous Tau in inducible mouse models of tauopathy. J. Neurosci. 28, 737-748.