title: Selective neuronal vulnerability and inadequate stress response in superoxide dismutase mutant mice.
abstract: To understand the role of oxidative stress and mitochondrial defects in the development of neurodegeneration, we examined the age-related pathological changes and corresponding gene expression profiles in homozygous mutant mice deficient in the mitochondrial form of superoxide dismutase (MnSOD, SOD2). These Sod2-/- mice, generated on a B6D2F1 background, developed ataxia at Postnatal Day (P) 11 and progressively deteriorated with frequent seizures by P14. Histopathological examination revealed neurodegenerative changes consistent with the neurological signs. Vacuolar degeneration was observed in neurons and neuropil throughout the brainstem and rostral cortex. The motor trigeminal nucleus in brainstem and the deeper layers of the motor cortex were the earliest regions to degenerate, with the thalamus and hippocampus affected at later stages. Oligonucleotide microarrays were used to compare gene expression profiles in the brainstem and thalamus of Sod2+/+ and -/- mice from birth to P18. Notably, a large set of heat-shock protein genes was transcriptionally down regulated, and this was most likely due to a reduction in the heat-shock transcription factor 1 (HSF1). Other major classes of differentially expressed genes include lipid biosynthesis and ROS metabolism.
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Lynn
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Huang
authors.forename: Sailaja
authors.initials: S
authors.lastname: Elchuri
authors.forename: Mohammed
authors.initials: M
authors.lastname: Naeemuddin
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Nishinaka
authors.forename: Junji
authors.initials: J
authors.lastname: Yodoi
authors.forename: Donna M
authors.initials: DM
authors.lastname: Ferriero
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Epstein
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Huang
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D001933:Brain Stem / Q000378:metabolism; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005609:Free Radicals; D005786:Gene Expression Regulation; D000076249:Heat Shock Transcription Factors; D007150:Immunohistochemistry; D050356:Lipid Metabolism; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D018482:Muscle, Skeletal / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D011485:Protein Binding; D012313:RNA / Q000378:metabolism; D017382:Reactive Oxygen Species; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000235:genetics / Q000502:physiology*; D013788:Thalamus / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors; D000099156:Superoxide Dismutase 2
chemical_list: D000975:Antioxidants; D004268:DNA-Binding Proteins; D005609:Free Radicals; D000076249:Heat Shock Transcription Factors; D012313:RNA; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D013879:Thioredoxins; D014157:Transcription Factors; D000099156:Superoxide Dismutase 2