SOD1 targeted to the mitochondrial intermembrane space prevents motor neuropathy in the Sod1 knockout mouse

Lindsey Hayes, Anissa Igoudjil, Jordi Magrané, Yingjie Li, Jason M. Hansen, Giovanni Manfredi, Jonathan D. Glass

Research output: Contribution to journalArticle

Abstract

Motor axon degeneration is a critical but poorly understood event leading to weakness and muscle atrophy in motor neuron diseases. Here, we investigated oxidative stress-mediated axonal degeneration in mice lacking the antioxidant enzyme, Cu,Zn superoxide dismutase (SOD1). We demonstrate a progressive motor axonopathy in these mice and show that Sod1-/- primary motor neurons extend short axons in vitro with reduced mitochondrial density. Sod1-/- neurons also show oxidation of mitochondrial - but not cytosolic - thioredoxin, suggesting that loss of SOD1 causes preferential oxidative stress in mitochondria, a primary source of superoxide in cells. SOD1 is widely regarded as the cytosolic isoform of superoxide dismutase, but is also found in the mitochondrial intermembrane space. The functional significance of SOD1 in the intermembrane space is unknown. We used a transgenic approach to express SOD1 exclusively in the intermembrane space and found that mitochondrial SOD1 is sufficient to prevent biochemical and morphological defects in the Sod1-/ - model, and to rescue the motor phenotype of these mice when followed to 12 months of age. These results suggest that SOD1 in the mitochondrial intermembrane space is fundamental for motor axon maintenance, and implicate oxidative damage initiated at mitochondrial sites in the pathogenesis of motor axon degeneration.

Original languageEnglish (US)
Pages (from-to)196-209
Number of pages14
JournalBrain
Volume134
Issue number1
DOIs
StatePublished - Jan 2011
Externally publishedYes

Fingerprint

Knockout Mice
Axons
Oxidative Stress
Motor Neuron Disease
Thioredoxins
Muscular Atrophy
Motor Neurons
Superoxides
Superoxide Dismutase
Mitochondria
Protein Isoforms
Antioxidants
Maintenance
Phenotype
Neurons
Enzymes

Keywords

  • axon
  • mitochondria
  • motor neuron disease
  • neuromuscular junction
  • SOD

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Hayes, L., Igoudjil, A., Magrané, J., Li, Y., Hansen, J. M., Manfredi, G., & Glass, J. D. (2011). SOD1 targeted to the mitochondrial intermembrane space prevents motor neuropathy in the Sod1 knockout mouse. Brain, 134(1), 196-209. https://doi.org/10.1093/brain/awq314

SOD1 targeted to the mitochondrial intermembrane space prevents motor neuropathy in the Sod1 knockout mouse. / Hayes, Lindsey; Igoudjil, Anissa; Magrané, Jordi; Li, Yingjie; Hansen, Jason M.; Manfredi, Giovanni; Glass, Jonathan D.

In: Brain, Vol. 134, No. 1, 01.2011, p. 196-209.

Research output: Contribution to journalArticle

Hayes, L, Igoudjil, A, Magrané, J, Li, Y, Hansen, JM, Manfredi, G & Glass, JD 2011, 'SOD1 targeted to the mitochondrial intermembrane space prevents motor neuropathy in the Sod1 knockout mouse', Brain, vol. 134, no. 1, pp. 196-209. https://doi.org/10.1093/brain/awq314
Hayes, Lindsey ; Igoudjil, Anissa ; Magrané, Jordi ; Li, Yingjie ; Hansen, Jason M. ; Manfredi, Giovanni ; Glass, Jonathan D. / SOD1 targeted to the mitochondrial intermembrane space prevents motor neuropathy in the Sod1 knockout mouse. In: Brain. 2011 ; Vol. 134, No. 1. pp. 196-209.
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