TY - JOUR A1 - Niemann, Axel A1 - Huber, Nina A1 - Wagner, Konstanze M. A1 - Somandin, Christian A1 - Horn, Michael A1 - Lebrun-Julien, Frédéric A1 - Angst, Brigitte A1 - Pereira, Jorge A. A1 - Halfter, Hartmut A1 - Welzl, Hans A1 - Feltri, M. Laura A1 - Wrabetz, Lawrence A1 - Young, Peter A1 - Wessig, Carsten A1 - Toyka, Klaus V. A1 - Suter, Ueli T1 - The Gdap1 knockout mouse mechanistically links redox control to Charcot–Marie–Tooth disease JF - Brain N2 - The ganglioside-induced differentiation-associated protein 1 (GDAP1) is a mitochondrial fission factor and mutations in GDAP1 cause Charcot–Marie–Tooth disease. We found that Gdap1 knockout mice (\(Gdap1^{−/−}\)), mimicking genetic alterations of patients suffering from severe forms of Charcot–Marie–Tooth disease, develop an age-related, hypomyelinating peripheral neuropathy. Ablation of Gdap1 expression in Schwann cells recapitulates this phenotype. Additionally, intra-axonal mitochondria of peripheral neurons are larger in \(Gdap1^{−/−}\) mice and mitochondrial transport is impaired in cultured sensory neurons of \(Gdap1^{−/−}\) mice compared with controls. These changes in mitochondrial morphology and dynamics also influence mitochondrial biogenesis. We demonstrate that mitochondrial DNA biogenesis and content is increased in the peripheral nervous system but not in the central nervous system of \(Gdap1^{−/−}\) mice compared with control littermates. In search for a molecular mechanism we turned to the paralogue of GDAP1, GDAP1L1, which is mainly expressed in the unaffected central nervous system. GDAP1L1 responds to elevated levels of oxidized glutathione by translocating from the cytosol to mitochondria, where it inserts into the mitochondrial outer membrane. This translocation is necessary to substitute for loss of GDAP1 expression. Accordingly, more GDAP1L1 was associated with mitochondria in the spinal cord of aged \(Gdap1^{−/−}\) mice compared with controls. Our findings demonstrate that Charcot–Marie–Tooth disease caused by mutations in GDAP1 leads to mild, persistent oxidative stress in the peripheral nervous system, which can be compensated by GDAP1L1 in the unaffected central nervous system. We conclude that members of the GDAP1 family are responsive and protective against stress associated with increased levels of oxidized glutathione. KW - animal models KW - Charcot-Marie-Tooth disease KW - mitochondria KW - axonal transport KW - demyelinating disease Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120731 VL - 137 IS - 3 ER - TY - JOUR A1 - Norrmen, Camilla A1 - Figlia, Gianluca A1 - Lebrun-Julien, Frederic A1 - Pereira, Jorge A. A1 - Trötzmüller, Martin A1 - Köfeler, Harald C. A1 - Rantanen, Ville A1 - Wessig, Carsten A1 - van Deijk, Anne-Lieke F. A1 - Smit, August B. A1 - Verheijen, Mark H. G. A1 - Rüegg, Markus A. A1 - Hall, Michael N. A1 - Suter, Ueli T1 - mTORC1 Controls PNS Myelination along the mTORC1-RXR gamma-SREBP-Lipid Biosynthesis Axis in Schwann Cells JF - Cell Reports N2 - Myelin formation during peripheral nervous system (PNS) development, and reformation after injury and in disease, requires multiple intrinsic and extrinsic signals. Akt/mTOR signaling has emerged as a major player involved, but the molecular mechanisms and downstream effectors are virtually unknown. Here, we have used Schwann-cell-specific conditional gene ablation of raptor and rictor, which encode essential components of the mTOR complexes 1 (mTORC1) and 2 (mTORC2), respectively, to demonstrate that mTORC1 controls PNS myelination during development. In this process, mTORC1 regulates lipid biosynthesis via sterol regulatory element-binding proteins (SREBPs). This course of action is mediated by the nuclear receptor RXRg, which transcriptionally regulates SREBP1c downstream of mTORC1. Absence of mTORC1 causes delayed myelination initiation as well as hypomyelination, together with abnormal lipid composition and decreased nerve conduction velocity. Thus, we have identified the mTORC1-RXR gamma-SREBP axis controlling lipid biosynthesis as a major contributor to proper peripheral nerve function. KW - axonal integrity KW - peripheral nervous-system KW - COMPLEX 1 KW - rat hepatocytes KW - SREBP KW - mice KW - growth KW - protein KW - element KW - CNS Myelination Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-114847 SN - 2211-1247 VL - 9 IS - 2 ER - TY - JOUR A1 - Meyer zu Hörste, Gerd A1 - Cordes, Steffen A1 - Mausberg, Anne K. A1 - Zozulya, Alla L. A1 - Wessig, Carsten A1 - Sparwasser, Tim A1 - Mathys, Christian A1 - Wiendl, Heinz A1 - Hartung, Hans-Peter A1 - Kieseier, Bernd C. T1 - FoxP3+Regulatory T Cells Determine Disease Severity in Rodent Models of Inflammatory Neuropathies JF - PLOS ONE N2 - Inflammatory neuropathies represent disabling human autoimmune disorders with considerable disease variability. Animal models provide insights into defined aspects of their disease pathogenesis. Forkhead box P3 (FoxP3)+ regulatory T lymphocytes (Treg) are anti-inflammatory cells that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. Dysfunction or a reduced frequency of Tregs have been associated with different human autoimmune disorders. We here analyzed the functional relevance of Tregs in determining disease manifestation and severity in murine models of autoimmune neuropathies. We took advantage of the DEREG mouse system allowing depletion of Treg with high specificity as well as anti-CD25 directed antibodies to deplete Tregs in mice in actively induced experimental autoimmune neuritis (EAN). Furthermore antibody-depletion was performed in an adoptive transfer model of chronic neuritis. Early Treg depletion increased clinical EAN severity both in active and adoptive transfer chronic neuritis. This was accompanied by increased proliferation of myelin specific T cells and histological signs of peripheral nerve inflammation. Late stage Treg depletion after initial disease manifestation however did not exacerbate inflammatory neuropathy symptoms further. We conclude that Tregs determine disease severity in experimental autoimmune neuropathies during the initial priming phase, but have no major disease modifying function after disease manifestation. Potential future therapeutic approaches targeting Tregs should thus be performed early in inflammatory neuropathies. KW - Guillain-Barre-Syndrome KW - regulatory cells KW - C57BL/6 mice KW - demyelinating polyradiculoneuropathy KW - cytokines KW - pathogenesis KW - polyneuropathy KW - enteropathy KW - peptide KW - experimental autoimmune neuritis Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-115239 VL - 9 IS - 10 ER -