Altered Reactivity of Superoxide Dismutase in Familial Amyotrophic Lateral Sclerosis

Wiedau‐Pazos, Martina; Goto, Joy J.; Rabizadeh, Shahrooz; Gralla, Edith Butler; Roe, James A.; Lee, Michael K.; Valentine, Joan Selverstone; Bredesen, Dale E.

doi:10.1126/science.271.5248.515

Cited by 683 publications

(387 citation statements)

References 22 publications

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“…Transgenic mouse models of ALS expressing mutant human SOD1 support human studies showing increased oxidative damage to mitochondrial proteins, lipids and DNA (reviewed in Barber and Shaw 2010). This has been explained by excessive dismutase activity of mutant SOD1 (Goldsteins et al 2008;Wiedau-Pazos et al 1996), increased levels of ROS produced by mitochondria following inhibition of complex I (Kruman et al 1999;Mattiazzi et al 2002;Murphy 2009;Zimmerman et al 2007), or increased NADPH oxidase (NOX) activity through mutant SOD1 interacting with Rac1, a NOX regulator (reviewed in Boillee and Cleveland 2008). It should be noted, however, that recent data indicate that overexpression of mutant SOD1 G93A in yeast cells actually provided increased protection against respiration-derived ROS (Kloppel et al 2010).…”

Section: Mitochondrial Morphological Abnormalities and Dysfunctions Imentioning

confidence: 95%

Mitochondrial dysfunction in familial amyotrophic lateral sclerosis

Faes¹,

Callewaert²

2011

J Bioenerg Biomembr

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A growing body of evidence suggests that mitochondrial dysfunctions play a crucial role in the pathogenesis of various neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting both upper and lower motor neurons. Although ALS is predominantly a sporadic disease, approximately 10% of cases are familial. The most frequent familial form is caused by mutations in the gene encoding Cu/Zn superoxide dismutase 1 (SOD1). A dominant toxic gain of function of mutant SOD1 has been considered as the cause of the disease and mitochondria are thought to be key players in the pathogenesis. However, the exact nature of the link between mutant SOD1 and mitochondrial dysfunctions remains to be established. Here, we briefly review the evidence for mitochondrial dysfunctions in familial ALS and discuss a possible link between mutant SOD1 and mitochondrial dysfunction.

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Section: Mitochondrial Morphological Abnormalities and Dysfunctions Imentioning

confidence: 95%

Mitochondrial dysfunction in familial amyotrophic lateral sclerosis

Faes¹,

Callewaert²

2011

J Bioenerg Biomembr

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“…In some familial ALS cases, mutations to the C u binding site of CdZn superoxide dismutase (SOD; superoxide oxidoreductase, EC 1.15.1 . l ) may increase the level of Cu-associated toxicity in motor neurons (Wiedau-Pazos et al, 1996;Yim et al, 1996;Ghadge et al, 1997;Zu et al, 1997).…”

mentioning

confidence: 99%

Exacerbation of Copper Toxicity in Primary Neuronal Cultures Depleted of Cellular Glutathione

White

Bush

Beyreuther

et al. 1999

Journal of Neurochemistry

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Perturbations to glutathione (GSH) metabolism may play an important role in neurodegenerative disorders such as Alzheimer's, Parkinson's, and prion diseases. A primary function of GSH is to prevent the toxic interaction between free radicals and reactive transition metals such as copper (Cu). Due to the potential role of Cu in neurodegeneration, we examined the effect of GSH depletion on Cu toxicity in murine primary neuronal cultures. Depletion of cellular GSH with L-buthionine-[S,R]-sulfoximine resulted in a dramatic potentiation of Cu toxicity in neurons without effect on iron (Fe) toxicity. Similarly, inhibition of glutathione reductase (GR) activity with 1,3-bis(2-chloroethyl)-l -nitrosurea also increased Cu toxicity in neurons. To determine if the Alzheimer's amyloid-p (Ap) peptide can affect neuronal resistance to transition metal toxicity, we exposed cultures to nontoxic concentrations of Ap25-35 in the presence or absence of Cu or Fe. Ap25-35 pretreatment was found to deplete neuronal GSH and increase GR activity, confirming the ability of Ap to perturb neuronal GSH homeostasis.Ap25-35 pretreatment potently increased Cu toxicity but had no effect on Fe toxicity. These studies demonstrate an important role for neuronal GSH homeostasis in selective protection against Cu toxicity, a finding with widespread implications for neurodegenerative disorders.

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“…It has been reported that the FALS mutants, G93A and A4V, exhibits an enhanced free radicalgenerating activity, while its dismutation activity is identical to that of the wild-type enzyme [12][13][14]. Previous results showed that the hydroxyl radical was generated in the reaction of human Cu,Zn-SOD with H202 [ 15].…”

Section: Resultsmentioning

confidence: 99%

The free radical‐generating function of a familial amyotrophic lateral sclerosis‐associated D90A Cu,Zn‐superoxide dismutase mutant

Kim¹,

Eum²,

Kwon³

et al. 1998

IUBMB Life

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SUMMARYThe free radical-generating functions of the D90A Cu,Zn-superoxide dismutase (SOD) associated with Swedish familial amyotrophic lateral sclerosis (FALS) patients are investigated. The results show that both the wild-type and mutant enzymes have identical dismutase activity, while the free radical-generating activity of the D90A mutant is enhanced relative to that of the wild-type enzyme. The studies suggest that the active channel of the D90A mutant is larger than that of the wild-type enzyme. A higher free radical-generating activity of the mutant enzyme led to the release of copper ions from the damaged protein. The generation of strand breaks in plasmid DNA was enhanced more effectively by the D90A mutant Cu,Zn-SOD than by the wildtype enzyme. The results suggest that the pathology of FALS may be attributed to oxidative damage caused by the gain-of-function of FALS Cu,Zn-SOD mutant.Key words: copper,zin-superoxide dismutase, mutant, hydroxyl radical, copper. 1191All rights of reproduction in any form reserved, Vol. 46, No. 6, 1998 BIOCHEMISTRY and MOLECULAR BIOLOGY INTERNATIONALAndersen et al. [7] reported a Cu,Zn-SOD exon 4 mutation (D90A) with novel features in Swedish FALS patients and the disease has only been observed in patients homozygous for this mutation, whereas heterozygotes remained unaffected. Furthermore, there was essentially no reduction in erythrocyte Cu,Zn-SOD dismutation activity. Thus, [7] suggested that this Cu,Zn-SOD mutation caused ALS by a gain-of-function rather than by the loss of dismutation activity.In view of these considerations, the present work represents an investigation of the free radical-generating functions of the D90A mutant and the oxidative damage to DNA, as a first attempt to establish the extent of any correlation between the gain-of-function and the pathology of FALS. MATERIALS AND METHODS Expression and purification of wild-type and mutated human Cu, Zn-SOD

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Altered Reactivity of Superoxide Dismutase in Familial Amyotrophic Lateral Sclerosis

Cited by 683 publications

References 22 publications

Mitochondrial dysfunction in familial amyotrophic lateral sclerosis

Mitochondrial dysfunction in familial amyotrophic lateral sclerosis

Exacerbation of Copper Toxicity in Primary Neuronal Cultures Depleted of Cellular Glutathione

The free radical‐generating function of a familial amyotrophic lateral sclerosis‐associated D90A Cu,Zn‐superoxide dismutase mutant

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