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The Gdap1 knockout mouse mechanistically links redox control to Charcot-Marie-tooth disease
- Source :
- Brain: A Journal of Neurology, 137 (3), Brain, Brain : a journal of neurology
- Publication Year :
- 2014
- Publisher :
- Oxford University Press, 2014.
-
Abstract
- Mutations in the mitochondrial fission factor GDAP1 are associated with severe peripheral neuropathies, but why the CNS remains unaffected is unclear. Using a Gdap1−/− mouse, Niemann et al. demonstrate that a CNS-expressed Gdap1 paralogue changes its subcellular localisation under oxidative stress conditions to also act as a mitochondrial fission factor.<br />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.
- Subjects :
- Mitochondrial DNA
10017 Institute of Anatomy
Central nervous system
610 Medicine & health
Mice, Transgenic
Nerve Tissue Proteins
Mitochondrion
Biology
medicine.disease_cause
Charcot-Marie-Tooth disease
DNA, Mitochondrial
demyelinating disease
Animal models
Axonal transport
Demyelinating disease
Mitochondria
Mice
medicine
Animals
ddc:610
Cells, Cultured
Mice, Knockout
Original Articles
medicine.disease
Glutathione
Axons
animal models
3. Good health
Cell biology
Cytosol
Disease Models, Animal
Oxidative Stress
2728 Neurology (clinical)
medicine.anatomical_structure
Phenotype
Biochemistry
Peripheral nervous system
Knockout mouse
570 Life sciences
biology
Neurology (clinical)
axonal transport
Oxidation-Reduction
Oxidative stress
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Brain: A Journal of Neurology, 137 (3), Brain, Brain : a journal of neurology
- Accession number :
- edsair.doi.dedup.....e43d753e92edc64508faa204766382f6