title: Overexpression of CCS in G93A-SOD1 mice leads to accelerated neurological deficits with severe mitochondrial pathology.
abstract: Cu, Zn superoxide dismutase (SOD1) has been detected within spinal cord mitochondria of mutant SOD1 transgenic mice, a model of familial ALS. The copper chaperone for SOD1 (CCS) provides SOD1 with copper, facilitates the conversion of immature apo-SOD1 to a mature holoform, and influences in yeast the cytosolic/mitochondrial partitioning of SOD1. To determine how CCS affects G93A-SOD1-induced disease, we generated transgenic mice overexpressing CCS and crossed them to G93A-SOD1 or wild-type SOD1 transgenic mice. Both CCS transgenic mice and CCS/wild-type-SOD1 dual transgenic mice are neurologically normal. In contrast, CCS/G93A-SOD1 dual transgenic mice develop accelerated neurological deficits, with a mean survival of 36 days, compared with 242 days for G93A-SOD1 mice. Immuno-EM and subcellular fractionation studies on the spinal cord show that G93A-SOD1 is enriched within mitochondria in the presence of CCS overexpression. Our results indicate that CCS overexpression in G93A-SOD1 mice produces severe mitochondrial pathology and accelerates disease course.
authors: Departments of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Marjatta
authors: M
authors: Son
authors: Krishna
authors: K
authors: Puttaparthi
authors: Hibiki
authors: H
authors: Kawamata
authors: Bhagya
authors: B
authors: Rajendran
authors: Philip J
authors: PJ
authors: Boyer
authors: Giovanni
authors: G
authors: Manfredi
authors: Jeffrey L
authors: JL
authors: Elliott
mesh_terms: D000818:Animals; D002458:Cell Fractionation; D003001:Cloning, Molecular; D003300:Copper / Q000378:metabolism*; D003433:Crosses, Genetic; D018076:DNA, Complementary; D018450:Disease Progression; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D008928:Mitochondria / Q000201:enzymology / Q000473:pathology* / Q000648:ultrastructure; D009046:Motor Neurons / Q000201:enzymology / Q000473:pathology* / Q000648:ultrastructure; D013116:Spinal Cord / Q000201:enzymology / Q000648:ultrastructure; D013347:Subcellular Fractions; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis
chemical_list: D018076:DNA, Complementary; D003300:Copper; D013482:Superoxide Dismutase