Intracellular ROS level is increased in fibroblasts of triple A syndrome patients.

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.