Strategies to halt the inflammation in X-linked adrenoleukodystrophy
X-linked adrenoleukodystrophy, macrophage, very long-chain fatty acids, inflammation, therapy, peroxisome
Dr. Berger’s main research focus is to understand the importance of different peroxisomal metabolic pathways for the proper function of the brain. Peroxisomal disorders can be categorized into peroxisome biogenesis disorders and single enzyme or transporter deficiencies, all of them affecting the central nervous system. One main focus concerns the most common peroxisomal disorder, X-linked adrenoleukodystrophy. The research is designed to elucidate molecular mechanisms underlying the different phenotypes of X-linked adrenoleukodystrophy and to develop novel therapeutic approaches. Another major focus is related to ether phospholipid biosynthesis, which is disturbed in a group of inherited peroxisomal disorders. Increasing evidence emerges suggesting a role of ether phospholipids in the pathogenesis of late onset neurodegenerative diseases such as Alzheimer’s disease. Thus, the characterization of molecular consequences of ether phospholipid deficiency for the nervous system is another focus of our laboratory.
Collaborating research groups where PhD Students can perform their research stay
- Aubourg Patrick, INSERM U986, University Paris-Descartes, Bicetre Hospital, Le Kremlin Bicetre, Paris, France;
- Eichler Florian, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street ACC 708, Boston, MA 02114, USA;
- Fatemi S Ali, Johns Hopkins Medical, Moser Center for Leukodystrophies and Neurogenetics Service, Kennedy Krieger Institute, Baltimore, USA
Know-how and infrastructure of the research group
Johannes Berger is an expert concerning the role of peroxisomes in health and disease. In cooperation with Dr. Klaus Nave (MPI, Göttingen, Germany), his group has developed a series of mouse models related to peroxisomal disorders and peroxisomal functions. These include several mouse models for X-linked adrenoleukodystrophy (Forss-Petter et al. 1997, Muneer et al. 2014). Also other mouse models, e.g. such for ether phospholipid deficiency or Alzheimer’s disease, are routinely used for in vivo analyses (Brodde et al. 2012, Facciotti et al. 2012). Primary cells from human patients (e.g. monocytes, lymphoblasts or fibroblasts) are employed for in vitro analysis of the role of peroxisomes in proper cell functioning (Wiesinger et al. 2013, Weber et al. 2014). A broad spectrum of biochemical, cell biological, and imaging techniques is regularly applied. One particularly unique technique established in our laboratory constitutes the purification of peroxisomes, using a series of different centrifugation steps followed by density gradient centrifugation. The procedure has been optimized for different kinds of tissues and cell types/lines. Another important tool is our large collection of primary fibroblasts from patients with peroxisomal disorders involving defects in the metabolism of branched-chain fatty acids, polyunsaturated fatty acids, dicaboxylic fatty acids, plasmalogens and very long-chain fatty acids caused by different mutations in individual enzymes, transporters or peroxins (the latter being responsible for peroxisomal biogenesis) (Kunze et al. 2011, Wiesinger et al. 2013, Dorninger et al. 2015). Messenger RNA quantification using a CFX96 multiplex Realtime RT-PCR System (e.g. Weber et al. 2014), as well as viability, oxidative stress and cell toxicity assays (GloMax Integrated System; Weinhofer et al., manuscript in preparation) are routinely used. Confocal microscope or animal housing facility including own equipment for quantification of motor performance are available within the center.