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  -