Non-native soluble oligomers of Cu/Zn superoxide dismutase (SOD1) contain a conformational epitope linked to cytotoxicity in amyotrophic lateral sclerosis (ALS)

Rachel L. Redler, Lanette Fee, James M. Fay, Michael Caplow, Nikolay Dokholyan

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Soluble misfolded Cu/Zn superoxide dismutase (SOD1) is implicated in motor neuron death in amyotrophic lateral sclerosis (ALS); however, the relative toxicities of the various non-native species formed by SOD1 as it misfolds and aggregates are unknown. Here, we demonstrate that early stages of SOD1 aggregation involve the formation of soluble oligomers that contain an epitope specific to disease-relevant misfolded SOD1; this epitope, recognized by the C4F6 antibody, has been proposed as a marker of toxic species. Formation of potentially toxic oligomers is likely to be exacerbated by an oxidizing cellular environment, as evidenced by increased oligomerization propensity and C4F6 reactivity when oxidative modification by glutathione is present at Cys-111. These findings suggest that soluble non-native SOD1 oligomers, rather than native-like dimers or monomers, share structural similarity to pathogenic misfolded species found in ALS patients and therefore represent potential cytotoxic agents and therapeutic targets in ALS.

Original languageEnglish (US)
Pages (from-to)2423-2432
Number of pages10
JournalBiochemistry
Volume53
Issue number14
DOIs
StatePublished - Apr 15 2014

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Amyotrophic Lateral Sclerosis
Cytotoxicity
Oligomers
Epitopes
Poisons
Oligomerization
Cytotoxins
Motor Neurons
Dimers
Neurons
Glutathione
Toxicity
Agglomeration
Monomers
Antibodies
Superoxide Dismutase
Superoxide Dismutase-1
Therapeutics

All Science Journal Classification (ASJC) codes

  • Biochemistry

Cite this

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title = "Non-native soluble oligomers of Cu/Zn superoxide dismutase (SOD1) contain a conformational epitope linked to cytotoxicity in amyotrophic lateral sclerosis (ALS)",
abstract = "Soluble misfolded Cu/Zn superoxide dismutase (SOD1) is implicated in motor neuron death in amyotrophic lateral sclerosis (ALS); however, the relative toxicities of the various non-native species formed by SOD1 as it misfolds and aggregates are unknown. Here, we demonstrate that early stages of SOD1 aggregation involve the formation of soluble oligomers that contain an epitope specific to disease-relevant misfolded SOD1; this epitope, recognized by the C4F6 antibody, has been proposed as a marker of toxic species. Formation of potentially toxic oligomers is likely to be exacerbated by an oxidizing cellular environment, as evidenced by increased oligomerization propensity and C4F6 reactivity when oxidative modification by glutathione is present at Cys-111. These findings suggest that soluble non-native SOD1 oligomers, rather than native-like dimers or monomers, share structural similarity to pathogenic misfolded species found in ALS patients and therefore represent potential cytotoxic agents and therapeutic targets in ALS.",
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Non-native soluble oligomers of Cu/Zn superoxide dismutase (SOD1) contain a conformational epitope linked to cytotoxicity in amyotrophic lateral sclerosis (ALS). / Redler, Rachel L.; Fee, Lanette; Fay, James M.; Caplow, Michael; Dokholyan, Nikolay.

In: Biochemistry, Vol. 53, No. 14, 15.04.2014, p. 2423-2432.

Research output: Contribution to journalArticle

TY - JOUR

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AU - Redler, Rachel L.

AU - Fee, Lanette

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AU - Caplow, Michael

AU - Dokholyan, Nikolay

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N2 - Soluble misfolded Cu/Zn superoxide dismutase (SOD1) is implicated in motor neuron death in amyotrophic lateral sclerosis (ALS); however, the relative toxicities of the various non-native species formed by SOD1 as it misfolds and aggregates are unknown. Here, we demonstrate that early stages of SOD1 aggregation involve the formation of soluble oligomers that contain an epitope specific to disease-relevant misfolded SOD1; this epitope, recognized by the C4F6 antibody, has been proposed as a marker of toxic species. Formation of potentially toxic oligomers is likely to be exacerbated by an oxidizing cellular environment, as evidenced by increased oligomerization propensity and C4F6 reactivity when oxidative modification by glutathione is present at Cys-111. These findings suggest that soluble non-native SOD1 oligomers, rather than native-like dimers or monomers, share structural similarity to pathogenic misfolded species found in ALS patients and therefore represent potential cytotoxic agents and therapeutic targets in ALS.

AB - Soluble misfolded Cu/Zn superoxide dismutase (SOD1) is implicated in motor neuron death in amyotrophic lateral sclerosis (ALS); however, the relative toxicities of the various non-native species formed by SOD1 as it misfolds and aggregates are unknown. Here, we demonstrate that early stages of SOD1 aggregation involve the formation of soluble oligomers that contain an epitope specific to disease-relevant misfolded SOD1; this epitope, recognized by the C4F6 antibody, has been proposed as a marker of toxic species. Formation of potentially toxic oligomers is likely to be exacerbated by an oxidizing cellular environment, as evidenced by increased oligomerization propensity and C4F6 reactivity when oxidative modification by glutathione is present at Cys-111. These findings suggest that soluble non-native SOD1 oligomers, rather than native-like dimers or monomers, share structural similarity to pathogenic misfolded species found in ALS patients and therefore represent potential cytotoxic agents and therapeutic targets in ALS.

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