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

Jian Liu, Concepción Lillo, P. Andreas Jonsson, Christine Vande Velde, Christopher M. Ward, Timothy M. Miller, Jamuna R. Subramaniam, Jeffrey D Rothstein, Stefan Marklund, Peter M. Andersen, Thomas Brännström, Ole Gredal, Philip Chun Wong, David S. Williams, Don W. Cleveland

Research output: Contribution to journalArticle

Abstract

One cause of amyotrophic lateral sclerosis (ALS) is mutation in ubiquitously expressed copper/zinc superoxide dismutase (SOD1), but the mechanism of toxicity to motor neurons is unknown. Multiple disease-causing mutants, but not wild-type SOD1, are now demonstrated to be recruited to mitochondria, but only in affected tissues. This is independent of the copper chaperone for SOD1 and dismutase activity. Highly preferential association with spinal cord mitochondria is seen in human ALS for a mutant SOD1 that accumulates only to trace cytoplasmic levels. Despite variable proportions that are successfully imported, nearly constant amounts of SOD1 mutants and covalently damaged adducts of them accumulate as apparent import intermediates and/or are tightly aggregated or crosslinked onto integral membrane components on the cytoplasmic face of those mitochondria. These findings implicate damage from action of spinal cord-specific factors that recruit mutant SOD1 to spinal mitochondria as the basis for their selective toxicity in ALS.

Original languageEnglish (US)
Pages (from-to)5-17
Number of pages13
JournalNeuron
Volume43
Issue number1
DOIs
StatePublished - Jul 8 2004

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Mitochondria
Amyotrophic Lateral Sclerosis
Copper
Spinal Cord
Cord Factors
Motor Neurons
Superoxide Dismutase
Zinc
Mutation
Membranes
Amyotrophic lateral sclerosis 1

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Liu, J., Lillo, C., Jonsson, P. A., Velde, C. V., Ward, C. M., Miller, T. M., ... Cleveland, D. W. (2004). Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria. Neuron, 43(1), 5-17. https://doi.org/10.1016/j.neuron.2004.06.016

Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria. / Liu, Jian; Lillo, Concepción; Jonsson, P. Andreas; Velde, Christine Vande; Ward, Christopher M.; Miller, Timothy M.; Subramaniam, Jamuna R.; Rothstein, Jeffrey D; Marklund, Stefan; Andersen, Peter M.; Brännström, Thomas; Gredal, Ole; Wong, Philip Chun; Williams, David S.; Cleveland, Don W.

In: Neuron, Vol. 43, No. 1, 08.07.2004, p. 5-17.

Research output: Contribution to journalArticle

Liu, J, Lillo, C, Jonsson, PA, Velde, CV, Ward, CM, Miller, TM, Subramaniam, JR, Rothstein, JD, Marklund, S, Andersen, PM, Brännström, T, Gredal, O, Wong, PC, Williams, DS & Cleveland, DW 2004, 'Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria', Neuron, vol. 43, no. 1, pp. 5-17. https://doi.org/10.1016/j.neuron.2004.06.016
Liu, Jian ; Lillo, Concepción ; Jonsson, P. Andreas ; Velde, Christine Vande ; Ward, Christopher M. ; Miller, Timothy M. ; Subramaniam, Jamuna R. ; Rothstein, Jeffrey D ; Marklund, Stefan ; Andersen, Peter M. ; Brännström, Thomas ; Gredal, Ole ; Wong, Philip Chun ; Williams, David S. ; Cleveland, Don W. / Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria. In: Neuron. 2004 ; Vol. 43, No. 1. pp. 5-17.
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