Overexpression of CCS in G93A-SOD1 mice leads to accelerated neurological deficits with severe mitochondrial pathology

Marjatta Son, Krishna Puttaparthi, Hibiki Kawamata, Bhagya Rajendran, Philip J. Boyer, Giovanni Manfredi, Jeffrey L. Elliott

Research output: Contribution to journalArticlepeer-review

119 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)6072-6077
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number14
DOIs
StatePublished - Apr 3 2007

Keywords

  • Aggregation
  • Amyotrophic lateral sclerosis
  • Motor neuron
  • Neurodegeneration
  • Transgenic

ASJC Scopus subject areas

  • General

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