Mutant Superoxide Dismutase-1-Linked Familial Amyotrophic Lateral Sclerosis: Molecular Mechanisms of Neuronal Death and Protection

Ghadge, Ghanashyam D.; Lee, J. P.; Bindokas, Vytautas P.; Jordán, Joaquı́n; Ma, Li; Miller, Richard J.

doi:10.1523/jneurosci.17-22-08756.1997

Cited by 176 publications

(144 citation statements)

References 37 publications

(49 reference statements)

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“…Mutations to the Cu binding site of CdZn SOD are responsible for some cases of inherited ALS. The mutations may increase the interaction of Cu with H,O,, resulting in increased toxicity with little change to cellular SOD activity (Yim et al, 1996;Ghadge et al, 1997;Yim et al, 1997). Moreover, the PrP protein, which is central to CJD, can bind Cu (Brown et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

“…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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“…Most studies on cell survival by Bcl-2 have reported using cell lines transfected with mutant SOD1 cDNA, 31,32 and a few using primary neuronal cultures. 33 In our experiment, we used primary neuronal cells with SOD1 mutation separated from wildtype neuronal cells.…”

Section: Figure 7 Detection Of Immunoreactivity For Bcl-2 In the Tongmentioning

confidence: 99%

Bcl-2 expression by retrograde transport of adenoviral vectors with Cre-loxP recombination system in motor neurons of mutant SOD1 transgenic mice

et al. 2001

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We investigated genes expression by retrograde axonal transport of replication-defective adenoviruses carrying genes for LacZ (AdLacZ) and Bcl-2 in motor neurons of transgenic mice expressing mutant human Cu/Zn superoxide dismutase (SOD1) gene containing a substitution of alanine for glycine at position 93. We found that intramuscular injection of AdLacZ into the tongue of mutant SOD1 transgenic mice and their wild-type littermates at various ages results in high expression of the transgene and similar time course of expression in hypoglossal cranial nerve nuclei, suggesting no difference in the behavior of the transgene expression between the two groups. Subsequently, we employed a molecular switching cassette for Bcl-2 designed to express Bcl-2 by Cre-loxP recombination using adenoviral vectors, and examined the COS7 and primary neuronal cells with the mutant SOD1 gene. The overexpression of Bcl-2 in

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“…Multiple groups have reported that SOD1 mutants cause death in primary neurons and neuronal cell lines (3)(4)(5). Currently, SOD1 mutants are considered to cause ALS by gain of toxic function, and various hypotheses have been proposed regarding SOD1 mutant-mediated neurotoxicity.…”

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confidence: 99%

Alsin, the Product of ALS2 Gene, Suppresses SOD1 Mutant Neurotoxicity through RhoGEF Domain by Interacting with SOD1 Mutants

Kanekura¹,

Hashimoto²,

Niikura³

et al. 2004

Journal of Biological Chemistry

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Mutation of the ALS2 gene encoding alsin is linked to the onset of autosomal recessive motor neuron diseases, including juvenile-onset amyotrophic lateral sclerosis (ALS). Alsin long form (LF) belongs to the family of the guanine nucleotide exchanging factor (GEF) for small GTPases. Expression of alsin LF, but not alsin short form, protected motor neuronal cells from toxicity induced by mutants of the Cu/Zn-superoxide dismutase (SOD1) gene, which cause autosomal dominant ALS. In contrast, expression of alsin did not suppress neurotoxicity by other neurodegenerative insults such as Alzheimer's disease-related genes. Deletion analysis of alsin LF demonstrated that the RhoGEF domain is essential for alsin-mediated neuroprotection. Furthermore, we found that alsin LF bound to SOD1 mutants, but not to wtSOD1, via the RhoGEF domain. Such functional and physical interaction between two ALS-related genes will become a promising clue to clarify the pathogenesis of ALS and other motor neuron diseases.

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Mutant Superoxide Dismutase-1-Linked Familial Amyotrophic Lateral Sclerosis: Molecular Mechanisms of Neuronal Death and Protection

Cited by 176 publications

References 37 publications

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

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

Bcl-2 expression by retrograde transport of adenoviral vectors with Cre-loxP recombination system in motor neurons of mutant SOD1 transgenic mice

Alsin, the Product of ALS2 Gene, Suppresses SOD1 Mutant Neurotoxicity through RhoGEF Domain by Interacting with SOD1 Mutants

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