Intracellular ROS level is increased in fibroblasts of triple A syndrome patients
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Triple A syndrome is named after the main symptoms of alacrima, achalasia, and adrenal insufficiency but also presents with a variety of neurological impairments. To investigate the causes of progressive neurodegeneration, we examined the oxidative status of fibroblast cultures derived from triple A syndrome patients in comparison to control cells. Patient cells showed a 2.1-fold increased basal level of reactive oxygen species (ROS) and a massive boost after induction of artificial oxidative stress by paraquat. We examined the expression of the ROS-detoxifying enzymes superoxide dismutase 1 and 2 (SOD1, SOD2), catalase, and glutathione reductase. The basal expression of SOD1 was significantly (1.3-fold) increased, and the expression of catalase was 0.7-fold decreased in patient cells after induction of artificial oxidative stress. We show that the mitochondrial network is 1.8-fold more extensive in patient cells compared to control fibroblasts although the maximal ATP synthesis was unchanged. Despite having the same energy potential as the controls, the patient cells showed a 1.4-fold increase in doubling time. We conclude that fibroblasts of triple A patients have a higher basal ROS level and an increased response to artificially induced oxidative stress and undergo “stress-induced premature senescence”. The increased sensitivity to oxidative stress may be a major mechanism for the neurodegeneration in triple A syndrome.
KeywordsFibroblasts Mitochondria Neurodegeneration Reactive oxygen species Triple A syndrome
We gratefully acknowledge Sandra Jackson from the Clinic of Neurology of the Technical University Dresden, Germany and Markus Schuelke from the Department of Neuropaediatrics of the Charité University Medicine, Berlin, Germany for the methodical help and fruitful discussions. This work was supported by a grant of the Deutsche Forschungsgemeinschaft (DFG, HU895 3/3–5) to AH and a MeDDrive grant of the Medical Faculty of the Technical University Dresden, Germany to KK.
Disclosure of potential conflict of interests
The authors declare no conflict of interests related to this study.
- 12.Neilson DE, Adams MD, Orr CM, Schelling DK, Eiben RM, Kerr DS, Anderson J, Bassuk AG, Bye AM, Childs AM et al (2009) Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2. Am J Hum Genet 84:44–51CrossRefPubMedGoogle Scholar
- 20.Cossarizza A, Salvioli S (2001) Flow cytometric analysis of mitochondrial membrane potential using JC-1. Curr Protoc Cytom 9.14Google Scholar
- 32.Lee HC, Wei YH (2007) Oxidative stress, mitochondrial DNA mutation, and apoptosis in aging. Exp Biol Med 232:592–606Google Scholar