Dr Werner Hoch

The molecular mechanisms underlying formation of functional heteromeric AMPA receptors from individual subunits and their intracellular processing and synaptic trafficing. In association with Jeremy Henley, Graham Collingridge and Elek Molnar, we are investigating how AMPA receptor subunits associate into hetero-oligomeric complexes. Many molecular properties of AMPA receptors, for example calcium permeability, mode of incorporation into synapses as well as recycling of these receptors critically depends on the presence or absence of different types of subunits. Our work is aimed at understanding the rules and specificity of the formation and synaptic targeting of AMPA receptor complexes with distinct subunit compositions. We are overexpressing individual epitope-tagged subunits or domains of subunits in nonneuronal and neuronal cells and assess their interaction with other subunits using a variety of biochemical and cell biological assays.

Role of Agrin and the Muscle-Specific Kinase (MuSK) during formation of the neuromuscular junction. We are studying how the motoneurone-derived basal membrane protein agrin activates the receptor tyrosine kinase MuSK. Activation of this kinase is the key event triggering postsynaptic differentiation on the myotube surface. This process can be monitored in tissue culture by visualizing the aggregation of nicotinic acetylcholine receptors. We serch for proteins interacting with activated MuSK and assess the mechanisms by which MuSK triggers the aggregation of these neurotransmitter receptors and other synaptic proteins.

The Muscle-Specific Kinase as target for autoantibodies in a new form of myasthenia gravis. The autoimmune disease myasthenia gravis is in most cases caused by antibodies directed against acetylcholine receptors. In about 15-20% of patients these antibodies cannot be detected. In collaboration with Angela Vincents group from Oxford university we have shown that in the majority of these seronegative patients autoantibodies directed against MuSK are present. We are currently studying the role of these antibodies for development of the disease.

Selected Recent publications

Hoch, W., McConville, J., Helms, S., Newsom-Davies, J., Melms, A. und Vincent, A. (2001) Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myastenia gravis without acetylcholine receptor antibodies. Nature Medicine, 7; 365-368.

Strochlic, L. Cartaud, A., Labas, V., Hoch, W., Rossier, J. und Cartaud, J. (2 001) MAGI 1C: a synaptic MAGUK interacting with MuSK at the vertebrate neuromuscular junction. J. Cell Biol.153; 1127-1132

Lück, G., Hoch, W. Hopf, C. und Blottner, D. (2000) Nitric oxide synthase (NOS1) coclustered to agrin-induced AChR-aggregates on cultured skeletal myotubes. Mol. Cell. Neurosci., 16; 269-281.

Hoch, W. (1999) Formation of the neuromuscular junction: Agrin and its unusual receptors. Eur. J. Biochem. 265; 1-11.

Leuschner, W. D. and Hoch, W. (1999) Subtype-specific assembly of AMPA receptor subunits is mediated by their N-terminal domains. J. Biol. Chem. 274; 16907-16916.

Hopf, C. and Hoch, W. (1998) Dimerization of the muscle specific kinase (MuSK) induces tyrosine phosphorylation of acetylcholine receptors and their aggregation on the surface of myotubes. J. Biol. Chem. 273; 6467-6473.

Hopf, C. and Hoch, W. (1998) Tyrosine phosphorylation of the muscle-specific kinase is exclusively induced by acetylcholine receptor-aggregating agrin fragments. Eur. J. Biochem. 253; 382-389.

Rohwedel, J., Kleppisch, T., Pich, U., Guan, K., Jin, S., Zuschratter, W., Hopf, C., Hoch, W., Hescheler, J., Witzemann, V. and Wobus, A. M. (1998) Formation of postsynaptic-like membranes during differentiation of embryonic stem cells in vitro. Exp. Cell Res. 239; 214-225.

Raats, C. J., Bakker, M. A. H., Hoch, W., Tamboer, W. P. M., Groffen, A. J. A., van den Heuvel, L. P.W. J., Berden, J. H. M. and van den Born, J. (1998) Differential expression of agrin in renal basement membranes as revealed by domain-specific antibodies. J. Biol. Chem. 273; 17832-17838.