title: Dysregulation of stathmin, a microtubule-destabilizing protein, and up-regulation of Hsp25, Hsp27, and the antioxidant peroxiredoxin 6 in a mouse model of familial amyotrophic lateral sclerosis.
abstract: Gain-of-function mutations of the Cu/Zn superoxide dismutase (SOD1) gene cause dominantly inherited familial amyotrophic lateral sclerosis. The identification of differentially regulated proteins in spinal cords of paralyzed mice expressing SOD1(G93A) may contribute to understanding mechanisms of toxicity by mutant SOD1. Protein profiling showed dysregulation of Stathmin with a marked decrease of its most acidic and phosphorylated isoform, and up-regulation of heat shock proteins 25 and 27, peroxiredoxin 6, phosphatidylinositol transfer protein-alpha, apolipoprotein E, and ferritin heavy chain. Stathmin accumulated in the cytoplasm of 30% of spinal cord motor neurons with fragmented Golgi apparatus. Overexpression of Stathmin in HeLa cells was associated with collapse of microtubule networks and Golgi fragmentation. These results, together with the decrease of one Stathmin isoform, suggest a role of the protein in Golgi fragmentation. Mutant SOD1 co-precipitated and co-localized with Hsp25 in neurons and astrocytes. Mutant SOD1 may thus deprive cells of the anti-apoptotic and other protective activities of Hsp25. Astrocytes contained peroxiredoxin 6, a unique nonredundant antioxidant. The up-regulation of peroxiredoxin 6 probably constitutes a defense to oxidative stress induced by SOD1(G93A). Direct effects of SOD1(G93A) or sequential reactions triggered by the mutant may cause the protein changes.
authors.affiliation: University of Pennsylvania Medical Center, 609 Stellar-Chance Labs., 422 Curie Blvd., Philadelphia, PA, 19104-6100, USA.
authors.forename: Christoph W
authors.initials: CW
authors.lastname: Strey
authors.forename: Daniel
authors.initials: D
authors.lastname: Spellman
authors.forename: Anna
authors.initials: A
authors.lastname: Stieber
authors.forename: Jacqueline O
authors.initials: JO
authors.lastname: Gonatas
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Wang
authors.forename: John D
authors.initials: JD
authors.lastname: Lambris
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Gonatas
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001253:Astrocytes / Q000378:metabolism; D015153:Blotting, Western; D015180:Electrophoresis, Gel, Two-Dimensional; D005786:Gene Expression Regulation; D006056:Golgi Apparatus / Q000378:metabolism; D055551:HSP27 Heat-Shock Proteins; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008868:Microtubule Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism; D008954:Models, Biological; D018832:Molecular Chaperones; D009046:Motor Neurons / Q000378:metabolism; D009154:Mutation; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism; D010544:Peroxidases / Q000096:biosynthesis*; D054465:Peroxiredoxin VI; D054464:Peroxiredoxins; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D013116:Spinal Cord / Q000378:metabolism; D050777:Stathmin; D014162:Transfection; D015854:Up-Regulation
chemical_list: D000975:Antioxidants; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; C486113:Hsbp1 protein, mouse; D008868:Microtubule Proteins; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D020033:Protein Isoforms; C493995:STMN1 protein, human; D050777:Stathmin; C493994:Stmn1 protein, mouse; D010544:Peroxidases; C515977:PRDX6 protein, human; D054465:Peroxiredoxin VI; D054464:Peroxiredoxins; C515983:Prdx6 protein, mouse