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When they fall ill, they are between the ages of 30 and 40. Common symptoms are poor balance when walking, impaired coordination of hand and leg movements, and unclear, slurred speech. These people suffer from spinocerebellar ataxia, an incurable hereditary nervous disorder of which there are more than 28 different forms. The symptoms are triggered by degenerating neurons in the cerebellum, the area of the brain that regulates the involuntary movements of the body. Cell death in spinocerebellar ataxia type 3 is caused by protein deposits in the neurons, which are formed from a pathogenic form of the protein ataxin-3 (Atx-3). Now, Dr. Annett Böddrich, a biochemist at the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch in the research group of Prof. Erich Wanker, and Dr. Sébastien Gaumer (research group of Prof. Nancy Bonini of the University of Pennsylvania, Philadelphia, USA, currently at the University of Versailles, France) have discovered that the pathogenic process of Atx-3 deposition might be influenced by the valosin-containing protein (VCP). Their research results have just been published in the EMBO Journal (Vol. 25, No. 7, pp. 1547 - 1558, 2006)*.
Within the protein Atx-3, the scientists succeeded in identifying one motif consisting of four basic amino acids which serves as a recognition site for VCP-interaction. VCP plays a role in vital processes in the cell, e.g. in the degradation of dysfunctional or no longer needed proteins. As demonstrated in vitro and also in experiments involving the Drosophila fruit fly, excess concentrations of VCP in proportion to Atx-3 suppress the formation of fibrils. By contrast, if VCP concentrations are too low in proportion to Atx-3, the fibril formation is stimulated. Thus, high VCP concentrations reduce Atx-3 protein aggregation in the retinal cells of the fruit fly and, in this way, prevent the degeneration of these cells. The molecular mechanism regulating how VCP mitigates the toxicity of pathogenic Atx-3 is still unclear. Here, further research promises to yield additional insights.
*An arginine/lysine-rich motif is crucial for VCP/p97-mediated modulation of ataxin-3 fibrillogenesis
Annett Boeddrich1,8, Sébastien Gaumer2,8,9, Annette Haacke3, Nikolay Tzvetkov3, Mario Albrecht4, Bernd O Evert5, Eva C Müller1, Rudi Lurz6, Peter Breuer3, Nancy Schugardt1, Stephanie Plaßmann1, Kexiang Xu2, John M Warrick2, Jaana Suopanki1, Ullrich Wüllner5, Ronald Frank7,10, Ulrich F Hartl3,10, Nancy M Bonini2,10 and Erich E Wanker1,10,*
1Department of Neuroproteomics, Max Delbrueck Center for Molecular Medicine (MDC), Berlin, Germany, 2Department of Biology, Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, PA,USA, 3Max Planck Institute for Biochemistry, Martinsried, Germany, 4Max Planck Institute for Informatics, Saarbrücken, Germany, 5Department of Neurology, University of Bonn, Bonn, Germany, 6Max Planck Institute for Molecular Genetics, Berlin, Germany and 7Department of Chemical Biology, GBF, Braunschweig, Germany
10 These are senior authors
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Research results, Scientific Publications
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