Neuronal redox imbalance results in altered energy homeostasis and early postnatal lethality. Issue 7 (31st March 2015)

• Record Type: Journal Article
• Authors: Maity‐Kumar, Gandhari; Thal, Dietmar R.; Baumann, Bernd; Scharffetter‐Kochanek, Karin; Wirth, Thomas
• Is Part Of: FASEB journal. Volume 29:Issue 7(2015)
• Page Start: 2843
• Page End: 2858
• Publication Date: 2015-03-31
• Subjects: neuronal apoptosis -- hypoglycemia -- oxidative stress -- SOD2; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.14-265157
• Languages: English
• ISSNs: 0892-6638

Abstract

ABSTRACT: Redox imbalance is believed to contribute to the development and progression of several neurodegenerative disorders. Our aim was to develop an animal model that exhibits neuron‐specific oxidative stress in the CNS to study the consequences and eventually find clues regarding the pathomechanisms of oxidative insults in neuronal homeostasis. We therefore generated a novel neuron‐specific superoxide dismutase 2 (SOD2)‐deficient mouse by deleting exon 3 of the SOD2 gene using CamKIIα promoter‐driven Cre expression. These neuron‐specific SOD2 knockout (SOD2 nko ) mice, although born at normal frequencies, died at the age of 4 weeks with critical growth retardation, severe energy failure, and several neurologic phenotypes. In addition, SOD2 nko mice exhibited severe neuronal alterations such as reactive astrogliosis, neuronal cell cycle inhibition, and induction of apoptosis. JNK activation and stabilization of p53, as a result of reactive oxygen species accumulation, are most likely the inducers of neuronal apoptosis in SOD2 nko mice. It is remarkable that hypothalamic regulation of glucose metabolism was affected, which in turn induced necrotic brain lesions in SOD2 nko mice. Taken together, our findings suggest that exclusive deficiency of SOD2 in neurons results in an impaired central regulation of energy homeostasis that leads to persistent hypoglycemia, hypoglycemia‐related neuropathology, and an early lethality of the mutant mice.—Maity‐Kumar, G., Thal, D. R., Baumann, B., Scharffetter‐Kochanek, K., Wirth, T. Neuronal redox imbalance results in altered energy homeostasis and early postnatal lethality. FASEB J . 29, 2843‐2858 (2015). www.fasebj.org