Charcot–Marie–Tooth disease CMT4A: GDAP1 increases cellular glutathione and the mitochondrial membrane potential

Noack, Rebecca; Frede, Svenja; Albrecht, Philipp; Henke, Nadine; Pfeiffer, Annika; Knoll, Kathrin; Dehmel, Thomas; Hörste, Gerd Meyer zu; Stettner, Mark; Kieseier, Bernd C.; Summer, Holger; Gölz, Stefan; Kochański, Andrzej; Wiedau‐Pazos, Martina; Arnold, Susanne; Lewerenz, Jan; Methner, Axel

doi:10.1093/hmg/ddr450

Cited by 79 publications

(108 citation statements)

References 41 publications

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“…50 Furthermore, wild type GDAP1 has been reported to protect against oxidative stress. 51 As the production of ROS also is a direct effect of alcohol intake, 52 this could be a potential link explaining GDAP1 hypomethylation in alcohol dependent patients: DNA hypomethylation should lead to increased expression and consequently increased protein production in alcohol dependent patients. Therefore, GDAP1 overexpression could counteract and compensate for the increased oxidative stress in alcohol dependence.…”

Section: Patients At T1 Patients At T2 P-valuementioning

confidence: 99%

Validation of differential GDAP1 DNA methylation in alcohol dependence and its potential function as a biomarker for disease severity and therapy outcome

et al. 2016

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Alcohol dependence is a severe disorder contributing substantially to the global burden of disease. Despite the detrimental consequences of chronic alcohol abuse and dependence, effective prevention strategies as well as treatment options are largely missing to date. Accumulating evidence suggests that gene-environment interactions, including epigenetic mechanisms, play a role in the etiology of alcohol dependence. A recent epigenome-wide study reported widespread alterations of DNA methylation patterns in alcohol dependent patients compared to control individuals. In the present study, we validate and replicate one of the top findings from this previous investigation in an independent cohort: the hypomethylation of GDAP1 in patients. To our knowledge, this is the first independent replication of an epigenome-wide finding in alcohol dependence. Furthermore, the AUDIT as well as the GSI score were negatively associated with GDAP1 methylation and we found a trend toward a negative association between GDAP1 methylation and the years of alcohol dependency, pointing toward a potential role of GDAP1 hypomethylation as biomarker for disease severity. In addition, we show that the hypomethylation of GDAP1 in patients reverses during a short-term alcohol treatment program, suggesting that GDAP1 DNA methylation could also serve as a potential biomarker for treatment outcome. Our data add to the growing body of knowledge on epigenetic effects in alcohol dependence and support GDAP1 as a novel candidate gene implicated in this disorder. As the role of GDAP1 in alcohol dependence is unknown, this novel candidate gene should be followed up in future studies.

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Section: Patients At T1 Patients At T2 P-valuementioning

confidence: 99%

Validation of differential GDAP1 DNA methylation in alcohol dependence and its potential function as a biomarker for disease severity and therapy outcome

et al. 2016

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“…Therefore, both reduced fission activity and enhanced elongation might shift the overall peroxisomal morphology towards a more tubular, less spherical phenotype. GDAP1 expression levels influence GSH levels in cultured cells [20], thereby potentially influencing peroxisomal biogenesis by increasing elongation due to cellular stress. Thus, we .05, **Po0.01, two-tailed unpaired t-test.…”

Section: Loss Of Gdap1 Reduces Peroxisomal Fragmentationmentioning

confidence: 99%

Charcot‐Marie‐Tooth disease‐associated mutants of GDAP1 dissociate its roles in peroxisomal and mitochondrial fission

et al. 2013

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Mitochondria and peroxisomes can be fragmented by the process of fission. The fission machineries of both organelles share a set of proteins. GDAP1 is a tail-anchored protein of mitochondria and induces mitochondrial fragmentation. Mutations in GDAP1 lead to Charcot-Marie-Tooth disease (CMT), an inherited peripheral neuropathy, and affect mitochondrial dynamics. Here, we show that GDAP1 is also targeted to peroxisomes mediated by the import receptor Pex19. Knockdown of GDAP1 leads to peroxisomal elongation that can be rescued by re-expressing GDAP1 and by missense mutated forms found in CMT patients. GDAP1-induced peroxisomal fission is dependent on the integrity of its hydrophobic domain 1, and on Drp1 and Mff, as is mitochondrial fission. Thus, GDAP1 regulates mitochondrial and peroxisomal fission by a similar mechanism. However, our results reveal also a more critical role of the amino-terminal GDAP1 domains, carrying most CMT-causing mutations, in the regulation of mitochondrial compared to peroxisomal fission.

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“…Of note, GSH depletion hampers the neutralization of ROS species. Thus, Gdap1 might increase the levels of GSH and decrease the production of ROS, by stabilizing the mitochondrial membrane potential and respiratory chain (104).…”

Section: Charcot-marie-tooth Neuropathiesmentioning

confidence: 99%

Iron Homeostasis in Peripheral Nervous System, Still a Black Box?

Levi

Taveggia²

2014

Antioxidants & Redox Signaling

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To stimulate research on iron metabolism and peripheral neuropathy, we provide a summary of the knowledge on iron homeostasis in the PNS, on its transport across the blood-nerve barrier, its involvement in myelination, and we identify unresolved questions. Furthermore, we comment on the role of iron in iron-related disorder with peripheral component, in demyelinating and metabolic peripheral neuropathies.

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Charcot–Marie–Tooth disease CMT4A: GDAP1 increases cellular glutathione and the mitochondrial membrane potential

Cited by 79 publications

References 41 publications

Validation of differential GDAP1 DNA methylation in alcohol dependence and its potential function as a biomarker for disease severity and therapy outcome

Validation of differential GDAP1 DNA methylation in alcohol dependence and its potential function as a biomarker for disease severity and therapy outcome

Charcot‐Marie‐Tooth disease‐associated mutants of GDAP1 dissociate its roles in peroxisomal and mitochondrial fission

Iron Homeostasis in Peripheral Nervous System, Still a Black Box?

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