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Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria

Jian Liu1, Concepción Lillo, P Andreas Jonsson

  • 1Ludwig Institute for Cancer Research, Department of Neurosciences, Medicine, and Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.

Neuron
|July 6, 2004
PubMed

Insights

Mutant copper/zinc superoxide dismutase (SOD1) proteins, a cause of amyotrophic lateral sclerosis (ALS), are recruited to spinal cord mitochondria, leading to motor neuron toxicity. This mitochondrial recruitment is linked to disease-specific factors.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease linked to mutations in the copper/zinc superoxide dismutase (SOD1) gene.
  • The precise mechanism by which mutant SOD1 causes motor neuron degeneration remains largely unknown.
  • SOD1 is ubiquitously expressed, but its toxicity in ALS appears to be restricted to specific tissues, particularly the spinal cord.

Purpose of the Study:

  • To investigate the cellular localization and potential mechanisms of toxicity for mutant SOD1 in the context of ALS.
  • To determine if mutant SOD1 is targeted to specific cellular organelles, such as mitochondria, in affected tissues.
  • To explore the role of mitochondrial recruitment and subsequent damage in the selective motor neuron pathology observed in ALS.

Main Methods:

  • Immunohistochemistry and biochemical assays were used to detect and quantify SOD1 protein localization in spinal cord tissues from ALS patients and controls.
  • Mitochondria were isolated from affected tissues to analyze SOD1 association and potential import intermediates.
  • The study examined the relationship between cytoplasmic SOD1 levels, mitochondrial import, and the formation of aggregated or crosslinked SOD1 adducts.

Main Results:

  • Disease-causing SOD1 mutants, but not wild-type SOD1, were found to be recruited to mitochondria, specifically in affected tissues like the spinal cord.
  • This mitochondrial recruitment occurred independently of the copper chaperone for SOD1 and its dismutase activity.
  • Mutant SOD1, even at trace cytoplasmic levels, showed preferential association with spinal cord mitochondria, accumulating as import intermediates or aggregated adducts on the mitochondrial surface.

Conclusions:

  • The selective toxicity of mutant SOD1 in ALS is implicated by its recruitment to spinal cord mitochondria.
  • Spinal cord-specific factors likely play a crucial role in targeting mutant SOD1 to mitochondria.
  • Damage resulting from the interaction of mutant SOD1 with spinal mitochondria is proposed as the basis for selective motor neuron toxicity in ALS.

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