title: Neuronal redox imbalance results in altered energy homeostasis and early postnatal lethality.
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.
authors.affiliation: *Institute of Physiological Chemistry and Laboratory of Neuropathology, Institute for Pathology, and Department of Dermatology and Allergology, University of Ulm, Ulm, Germany.
authors.forename: Gandhari
authors.initials: G
authors.lastname: Maity-Kumar
authors.affiliation: *Institute of Physiological Chemistry and Laboratory of Neuropathology, Institute for Pathology, and Department of Dermatology and Allergology, University of Ulm, Ulm, Germany.
authors.forename: Dietmar R
authors.initials: DR
authors.lastname: Thal
authors.affiliation: *Institute of Physiological Chemistry and Laboratory of Neuropathology, Institute for Pathology, and Department of Dermatology and Allergology, University of Ulm, Ulm, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Baumann
authors.affiliation: *Institute of Physiological Chemistry and Laboratory of Neuropathology, Institute for Pathology, and Department of Dermatology and Allergology, University of Ulm, Ulm, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Scharffetter-Kochanek
authors.affiliation: *Institute of Physiological Chemistry and Laboratory of Neuropathology, Institute for Pathology, and Department of Dermatology and Allergology, University of Ulm, Ulm, Germany thomas.wirth@uni-ulm.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wirth
mesh_terms: D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004734:Energy Metabolism; D005260:Female; D006706:Homeostasis; D007003:Hypoglycemia / Q000378:metabolism / Q000473:pathology; D007031:Hypothalamus / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000172:deficiency* / Q000235:genetics; D000099156:Superoxide Dismutase 2
chemical_list: D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2
keywords: SOD2; hypoglycemia; neuronal apoptosis; oxidative stress