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Brain-Specific Superoxide Dismutase 2 Deficiency Causes Perinatal Death with Spongiform Encephalopathy in Mice.

Izuo N, Nojiri H, Uchiyama S, Noda Y, Kawakami S, Kojima S, Sasaki T, Shirasawa T, Shimizu T - Oxid Med Cell Longev (2015)

Bottom Line: Manganese superoxide dismutase (Mn-SOD, SOD2) is a mitochondrial antioxidant enzyme that converts toxic superoxide to hydrogen peroxide.B-Sod2(-/-) showed perinatal death, along with severe growth retardation.Furthermore, brain lipid peroxidation was significantly increased in the B-Sod2(-/-), without any compensatory alterations of the activities of other antioxidative enzymes, such as catalase or glutathione peroxidase.

View Article: PubMed Central - PubMed

Affiliation: Department of Advanced Aging Medicine, Chiba University Graduate School of Medicine, Inohana, Chuo-ku, Chiba 260-8670, Japan.

ABSTRACT
Oxidative stress is believed to greatly contribute to the pathogenesis of various diseases, including neurodegeneration. Impairment of mitochondrial energy production and increased mitochondrial oxidative damage are considered early pathological events that lead to neurodegeneration. Manganese superoxide dismutase (Mn-SOD, SOD2) is a mitochondrial antioxidant enzyme that converts toxic superoxide to hydrogen peroxide. To investigate the pathological role of mitochondrial oxidative stress in the central nervous system, we generated brain-specific SOD2-deficient mice (B-Sod2(-/-)) using nestin-Cre-loxp system. B-Sod2(-/-) showed perinatal death, along with severe growth retardation. Interestingly, these mice exhibited spongiform neurodegeneration in motor cortex, hippocampus, and brainstem, accompanied by gliosis. In addition, the mutant mice had markedly decreased mitochondrial complex II activity, but not complex I or IV, in the brain based on enzyme histochemistry. Furthermore, brain lipid peroxidation was significantly increased in the B-Sod2(-/-), without any compensatory alterations of the activities of other antioxidative enzymes, such as catalase or glutathione peroxidase. These results suggest that SOD2 protects the neural system from oxidative stress in the perinatal stage and is essential for infant survival and central neural function in mice.

No MeSH data available.


Related in: MedlinePlus

B-Sod2−/− exhibited distinct spongiform encephalopathy in the brain. (a–f) Coronal sections of brains from three-week-old B-Sod2−/−. Motor cortex (a, d), hippocampus (b, e), and brain stem (c, f). A large number of vacuoles were morphologically observed in B-Sod2−/−. Higher power views (inset) showed neuronal degeneration and malformation with cytoplasmic vacuolization, as well as pleomorphic nuclei (d, e, and f). The scale bars indicate 200 μm.
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fig2: B-Sod2−/− exhibited distinct spongiform encephalopathy in the brain. (a–f) Coronal sections of brains from three-week-old B-Sod2−/−. Motor cortex (a, d), hippocampus (b, e), and brain stem (c, f). A large number of vacuoles were morphologically observed in B-Sod2−/−. Higher power views (inset) showed neuronal degeneration and malformation with cytoplasmic vacuolization, as well as pleomorphic nuclei (d, e, and f). The scale bars indicate 200 μm.

Mentions: Next, we prepared brain coronal sections from three-week-old B-Sod2−/−, conducting the histochemical analysis. Hematoxylin and eosin staining revealed vacuolization similar to spongiform encephalopathy selectively in cerebral motor cortex, hippocampus, and brain stem in B-Sod2−/−, but not in control (Figure 2). This abnormal vacuolization probably resulted from neuronal degeneration due to the susceptibility to oxidative stress. In addition to the vacuolization, we observed that the number of glial fibrillary acidic protein (GFAP) positive cells was increased in cerebral cortex (Figure 3) and hippocampus (data not shown) in B-Sod2−/− by immunohistochemical analysis, thus suggesting astrocyte activation. These results suggest that the biological function of SOD2 is essential for preventing neurodegeneration and astrocyte activation.


Brain-Specific Superoxide Dismutase 2 Deficiency Causes Perinatal Death with Spongiform Encephalopathy in Mice.

Izuo N, Nojiri H, Uchiyama S, Noda Y, Kawakami S, Kojima S, Sasaki T, Shirasawa T, Shimizu T - Oxid Med Cell Longev (2015)

B-Sod2−/− exhibited distinct spongiform encephalopathy in the brain. (a–f) Coronal sections of brains from three-week-old B-Sod2−/−. Motor cortex (a, d), hippocampus (b, e), and brain stem (c, f). A large number of vacuoles were morphologically observed in B-Sod2−/−. Higher power views (inset) showed neuronal degeneration and malformation with cytoplasmic vacuolization, as well as pleomorphic nuclei (d, e, and f). The scale bars indicate 200 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4537744&req=5

fig2: B-Sod2−/− exhibited distinct spongiform encephalopathy in the brain. (a–f) Coronal sections of brains from three-week-old B-Sod2−/−. Motor cortex (a, d), hippocampus (b, e), and brain stem (c, f). A large number of vacuoles were morphologically observed in B-Sod2−/−. Higher power views (inset) showed neuronal degeneration and malformation with cytoplasmic vacuolization, as well as pleomorphic nuclei (d, e, and f). The scale bars indicate 200 μm.
Mentions: Next, we prepared brain coronal sections from three-week-old B-Sod2−/−, conducting the histochemical analysis. Hematoxylin and eosin staining revealed vacuolization similar to spongiform encephalopathy selectively in cerebral motor cortex, hippocampus, and brain stem in B-Sod2−/−, but not in control (Figure 2). This abnormal vacuolization probably resulted from neuronal degeneration due to the susceptibility to oxidative stress. In addition to the vacuolization, we observed that the number of glial fibrillary acidic protein (GFAP) positive cells was increased in cerebral cortex (Figure 3) and hippocampus (data not shown) in B-Sod2−/− by immunohistochemical analysis, thus suggesting astrocyte activation. These results suggest that the biological function of SOD2 is essential for preventing neurodegeneration and astrocyte activation.

Bottom Line: Manganese superoxide dismutase (Mn-SOD, SOD2) is a mitochondrial antioxidant enzyme that converts toxic superoxide to hydrogen peroxide.B-Sod2(-/-) showed perinatal death, along with severe growth retardation.Furthermore, brain lipid peroxidation was significantly increased in the B-Sod2(-/-), without any compensatory alterations of the activities of other antioxidative enzymes, such as catalase or glutathione peroxidase.

View Article: PubMed Central - PubMed

Affiliation: Department of Advanced Aging Medicine, Chiba University Graduate School of Medicine, Inohana, Chuo-ku, Chiba 260-8670, Japan.

ABSTRACT
Oxidative stress is believed to greatly contribute to the pathogenesis of various diseases, including neurodegeneration. Impairment of mitochondrial energy production and increased mitochondrial oxidative damage are considered early pathological events that lead to neurodegeneration. Manganese superoxide dismutase (Mn-SOD, SOD2) is a mitochondrial antioxidant enzyme that converts toxic superoxide to hydrogen peroxide. To investigate the pathological role of mitochondrial oxidative stress in the central nervous system, we generated brain-specific SOD2-deficient mice (B-Sod2(-/-)) using nestin-Cre-loxp system. B-Sod2(-/-) showed perinatal death, along with severe growth retardation. Interestingly, these mice exhibited spongiform neurodegeneration in motor cortex, hippocampus, and brainstem, accompanied by gliosis. In addition, the mutant mice had markedly decreased mitochondrial complex II activity, but not complex I or IV, in the brain based on enzyme histochemistry. Furthermore, brain lipid peroxidation was significantly increased in the B-Sod2(-/-), without any compensatory alterations of the activities of other antioxidative enzymes, such as catalase or glutathione peroxidase. These results suggest that SOD2 protects the neural system from oxidative stress in the perinatal stage and is essential for infant survival and central neural function in mice.

No MeSH data available.


Related in: MedlinePlus