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Wilhelm Just Goal The work of the group focuses on two main topics (i) mechanisms involved in peroxisome proliferation and (ii) the physiological role of ether lipids (ELs) particularly plasmalogens (PLs), the most abundant EL species in mam- mals. Studies on peroxisome biogenesis and functioning are important in terms of both basic biological understanding of eukaryotic cells and human pathology. Background In the last years we accumulated data indicating an autonomous division of peroxisomes. To learn more about the mechanisms implicated in this process, we initiated experiments to identify the components involved. Most functions attributed to PLs thus far were derived from in vitro experiments. We used the ELdeficient mouse recently generated in our laboratory as a promising model to study EL functions in vivo. Research Highlights Ultrastructural analysis of proliferating rat liver peroxisomes revealed formation of multiple constrictions in tubular peroxisomes resembling a presegregational state (Lay D. et al., 2006) (Fig. 1). 16 Wilhelm Just 1970 - 1978 Group leader at the Max-Planck-Institute of Brain Research, Frankfurt/M. since 1978 Group leader at the Institute of Biochemistry I / Biochemie- Zentrum der Universität Heidelberg (BZH) 1987 Habilitation in Biochemistry at the University of Heidelberg since 1994 Professor at the Biochemie-Zentrum der Universität Heidelberg (BZH) Functions and Biogenesis of Peroxisomes Fig. 1: Peroxisomal constrictions at an early (A) and later (B) stage of tubulated peroxisomes. Factors potentially implicated in this process include various Arf and Rab isotypes, RhoA, actin and myosin (Lay D. et al., 2005; Wiese S. et al., 2007) as well as ATP and distinct phosphoinositide kinases and phosphatases (Jeynov B. et al., Fig. 2: Model showing putative sites of action of Arf1/ COPI as well as phosphoinositides, actin, myosin and dynamin-like protein 1 during vesicular shuttling between peroxisomes and the ER (Lay, 2006, Lay, 2005) and peroxisome proliferation (Wiese, Jeynov), respectively. Alternatively, cycles of Arf/COPI binding and release may facilitate formation of protein clusters and/or interaction with the cytoskeleton.
2006). These factors were used to draw a model showing their putative sites of action (Fig. 2). We also continued to investigate the effect of PL deficiency on CNS myelination in cortex and cerebellum. In both regions we noted a delay in myelination that was most conspicuous in peripheral cortical layers (Fig. 3). Fig. 3: Dysmyelination in cortex and cerebellum of P20 control (+/+) and EL-deficient mice (-/-). Dysmyelination was accompanied by reduced concentrations of MBP as well as a significantly impaired nerve conduction velocity as determined in fibers of the corpus callosum (Gorgas K. et al., 2006; Liu D. et al., 2005). Whereas Nav- and Kv-channels were normally distributed, axonal swellings and formation of axon varicosities suggest defects in organelle transport and/or Ca2+signaling (Fig. 4). Fig. 4: Varicosities (arrows, and inset) in Purkinje cell axons of P45 EL-deficient mice. Selected Publications 2004 - 2007 S. Wiese, T. Gronemeyer, R. Ofman, M. Kunze, C P. Grou, J. A. Almeida, M. Eisenacher, C. Stephan, H. Hayen, L. Schollenberger, T. Korosec, H. R. Waterham, W. Schliebs, R. Erdmann, J. Berger, H. E. Meyer, W. W. Just, J. E. Azevedo, R. J. A. Wanders, B. Warscheid. 2007. Proteomic characterization of mouse kidney peroxisomes by tandem mass spectrometry and protein correlation profiling. Mol Cell Proteomics. 6, 2045-57. Lay, D, K. Gorgas, W. W. Just. 2006. Peroxisome biogenesis: Where Arf and coatomer might be involved. BBAMCR, 1763, 1678-1687. Jeynov B, D. Lay, F. Schmidt, S. Tahirovic, W. W. Just. 2006. Phosphoinositide synthesis and degradation in isolated rat liver peroxisomes. FEBS Lett. 580, 5917-5924. Gorgas, K, A. Teigler, D. Komljenovic, W. W. Just. 2006. The ether lipid-deficient mouse: Tracking down plasmalogen functions. BBAMCR, 1763, 1511-1526. Lay D, B. L. Grosshans, H. Heid, K. Gorgas, W. W. Just. 2005. Binding and functions of ARF on mammalian and yeast peroxisomes. J Biol Chem. 280, 34489-34499. Liu D, N. Nagan, W. W. Just, C. Rodemer, T-P. Thai, R. A. Zoeller. 2005. Role of dihydroxyacetonephosphate acyltransferase in the biosynthesis of plasmalogens and nonether glycerolipids. J Lipid Res. 46, 727-735. Wilhelm Just Biochemie-Zentrum der Universität Heidelberg (BZH) Im Neuenheimer Feld 328 D-69120 Heidelberg Phone Office: +49 (0)6221-54 4151 Phone Lab: +49 (0)6221-54 5419 Fax: +49 (0)6221-54 4366 E-mail: wilhelm.just@bzh.uni-heidelberg.de Wilhelm Just 17
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