Evidence of Increased Oxidative Damage in Both Sporadic and Familial Amyotrophic Lateral Sclerosis

Rj, Ferrante; Se, Browne; La, Shinobu; Ac, Bowling; Mj, Baik; MacGarvey, Usha; Nw, Kowall; Brown, R. H.; Mf, Beal

doi:10.1046/j.1471-4159.1997.69052064.x

Cited by 700 publications

(407 citation statements)

References 56 publications

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“…3). A number of studies have established an association between oxidative stress and fALS; an increase in protein carbonyl content and reactive oxygen species was demonstrated in fALS patients and transgenic mouse model (18,19). Oxidative stress is shown further to augment the SOD1 aggregation in cell culture models; high MM and insoluble SOD1 species become evident when the neuronal cells expressing ALS-mutant SOD1 are exposed to increasing concentration of H 2 O 2 (37).…”

Section: Discussionmentioning

confidence: 99%

“…A disulfide bond also is introduced into WT SOD1 upon oxidative stress, but it is introduced correctly in an intramolecular fashion, which leads to protein stabilization and activation (17). In fact, increased oxidative stress has been reported in the neuronal tissues of SOD1-related fALS patients (18) and transgenic mouse models (19), which would aggravate formation of the disulfide-linked SOD1 multimers. Disulfide-linked multimerization of the SOD1 molecules, thus, would be an important gain of toxic properties with ALS mutations.…”

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confidence: 99%

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Disulfide cross-linked protein represents a significant fraction of ALS-associated Cu, Zn-superoxide dismutase aggregates in spinal cords of model mice

Furukawa¹,

Deng

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

193

184

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Point mutations in Cu, Zn-superoxide dismutase (SOD1) cause a familial form of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Aggregates of mutant SOD1 proteins are observed in histopathology and are invoked in several proposed mechanisms for motor neuronal death; however, the significant stability and activity of the mature mutant proteins are not readily explained in such models. Recent biochemical studies suggest that it is the immature disulfide-reduced forms of the familial ALS mutant SOD1 proteins that play a critical role; these forms tend to misfold, oligomerize, and readily undergo incorrect disulfide formation upon mild oxidative stress in vitro. Here we provide physiological support for this mechanism of aggregate formation and show that a significant fraction of the insoluble SOD1 aggregates in spinal cord of the ALS-model transgenic mice contain multimers cross-linked via intermolecular disulfide bonds. These insoluble disulfide-linked SOD1 multimers are found only in the spinal cord of symptomatic transgenic animals, are not observed in unafflicted tissue such as brain cortex and liver, and can incorporate WT SOD1 protein. The findings provide a biochemical basis for a pathological hallmark of this disease; namely, incorrect disulfide cross-linking of the immature, misfolded mutant proteins leads to insoluble aggregates. disulfide bond ͉ protein aggregation ͉ oxidative stress ͉ neurodegnerative disease A myotrophic lateral sclerosis (ALS) is one of the most common adult-onset neurodegenerative diseases, and, in 1993, several mutations in the Cu, Zn-superoxide dismutase (SOD1) gene were identified as a cause of a subset of familial ALS (fALS) (1, 2). Since that time, Ͼ100 types of SOD1 mutations have been linked with fALS; however, its molecular mechanism remains unresolved. SOD1, which is a homodimer with a copper and zinc ion in each subunit, functions as an antioxidant enzyme by converting superoxide radical to oxygen and hydrogen peroxide (3). Some of the SOD1 mutant proteins have comparable levels of dismutase activity, and the SOD1-knockout mouse does not develop ALS-like motor neuron symptoms (4), leading to the idea that SOD1-mediated toxicity in fALS is due to a new activity acquired by mutations in the SOD1 gene. One of the proposed toxic functions in the SOD1 mutant proteins is an aberrant copper chemistry. A subset of ALS mutations in SOD1 can lead to catalytic nitration of tyrosine residues and peroxide or superoxide production at the copper site (5); however, the copper-toxicity model is difficult to reconcile with the fact that ALS symptoms still are observed in the transgenic mouse expressing SOD1 proteins in which all four copper ligands are mutated (6). Although some copper chelators can reduce the toxicity of mutant proteins in transgenic ALS model mice (7), a role for aberrant copper chemistry in the disease has not been widely addressed.Another hypothesis for a gain of toxic function is that the mutations in SOD1 facilitate protein aggregation (8). An enzyma...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Disulfide cross-linked protein represents a significant fraction of ALS-associated Cu, Zn-superoxide dismutase aggregates in spinal cords of model mice

Furukawa¹,

Deng

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

193

184

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“…3 It is well accepted that Oxidative stress contributes to the pathogenesis of ALS. [4][5][6] Nuclear factor erythroid 2-related factor 2 (Nrf2), a member of the 'cap 'n' collar' family of basic leucine zipper transcription factors, 7 binds to antioxidant response element (ARE) in the upstream region of its target genes promoting transcription of various cytoprotective genes, such as heme oxygenase-1 (HO-1), 8 NAD(P)H: quinone oxidoreductase 1 (NQO1), 9 and the catalytic subunit of glutamate cysteine ligase (GCLC), 10 which helps restore the oxidant-antioxidant balance in cells. 10,11 In this context, several studies demonstrated that Nrf2/ARE activators provided robust neuroprotective effect and ameliorated the disease progression in SOD1-G93A transgenic mice.…”

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confidence: 99%

The modest impact of transcription factor Nrf2 on the course of disease in an ALS animal model

Guo

Zhang

Wen

et al. 2013

Laboratory Investigation

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“…Several hypotheses have been proposed to explain this toxic gain of function of mutated Cu,Zn-SOD in FALS (6,18,19,29). For example, oxidative stress produced by aberrant catalysis (13,36), abnormal Cu chemistry (26), decreased glutamate metabolism (6), and increased cytoplasmic aggregation (7,11,18,20,26,29) have been studied in the setting of mutated Cu,Zn-SOD. However, the precise mechanism of pathogenesis is not understood.…”

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confidence: 99%

Overexpression of mutated Cu,Zn-SOD in neuroblastoma cells results in cytoskeletal change

Takamiya

Takahashi²,

Park³

et al. 2005

American Journal of Physiology-Cell Physiology

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Amyotrophic lateral sclerosis (ALS) involves the progressive degeneration of motor neurons in the spinal cord and the motor cortex. It has been shown that 15–20% of patients with familial ALS (FALS) have defects in the Sod1 gene, which encodes Cu,Zn-superoxide dismutase (SOD). To elucidate the pathological role of mutated Cu,Zn-SOD, we examined the issue of whether mutated Cu,Zn-SOD affects the cell cycle. Mouse neuroblastoma Neuro-2a cells were transfected with human wild-type or mutated (G37R, G93A) Cu,Zn-SOD. Mutated, Cu,Zn-SOD-transfected cells exhibited marked retardation in cell growth and G2/M arrest. They also displayed lower reactivity to phalloidin, indicating that the cytoskeleton was disrupted. Immunoprecipitation, two-dimensional gel electrophoresis, and Western blot analysis indicated that mutated Cu,Zn-SOD associates with actin. Similar results were obtained by in vitro incubation experiments with purified actin and mutated Cu,Zn-SOD (G93A). These results suggest that mutated Cu,Zn-SOD in FALS causes cytoskeletal changes by associating with actin, which subsequently causes G2/M arrest and growth retardation.

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Evidence of Increased Oxidative Damage in Both Sporadic and Familial Amyotrophic Lateral Sclerosis

Cited by 700 publications

References 56 publications

Disulfide cross-linked protein represents a significant fraction of ALS-associated Cu, Zn-superoxide dismutase aggregates in spinal cords of model mice

Disulfide cross-linked protein represents a significant fraction of ALS-associated Cu, Zn-superoxide dismutase aggregates in spinal cords of model mice

The modest impact of transcription factor Nrf2 on the course of disease in an ALS animal model

Overexpression of mutated Cu,Zn-SOD in neuroblastoma cells results in cytoskeletal change

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