The Gdap1 knockout mouse mechanistically links redox control to Charcot-Marie-Tooth disease.
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.
1 Institute of Molecular Health Sciences, Cell Biology, Department of Biology, ETH Zurich, Swiss Federal Institute of Technology, Switzerland, ETH-Hönggerberg, 8093 Zürich, Switzerland.
Axel
A
Niemann
Nina
N
Huber
Konstanze M
KM
Wagner
Christian
C
Somandin
Michael
M
Horn
Frédéric
F
Lebrun-Julien
Brigitte
B
Angst
Jorge A
JA
Pereira
Hartmut
H
Halfter
Hans
H
Welzl
M Laura
ML
Feltri
Lawrence
L
Wrabetz
Peter
P
Young
Carsten
C
Wessig
Klaus V
KV
Toyka
Ueli
U
Suter
D000818:Animals; D001369:Axons / Q000378:metabolism*; D002478:Cells, Cultured; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004272:DNA, Mitochondrial / Q000235:genetics; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010641:Phenotype
D004272:DNA, Mitochondrial; C118663:GDAP protein; D009419:Nerve Tissue Proteins; D005978:Glutathione
Charcot-Marie-Tooth disease; animal models; axonal transport; demyelinating disease; mitochondria