Exacerbation of Delayed Cell Injury After Transient Global Ischemia in Mutant Mice With CuZn Superoxide Dismutase Deficiency

Kawase, Makoto; Murakami, Kensuke; Fujimura, Miki; Morita-Fujimura, Yuiko; Gasche, Yvan; Kondo, Takeo; Scott, Richard W.; Chan, Pak H.

doi:10.1161/01.str.30.9.1962

Cited by 131 publications

(85 citation statements)

References 36 publications

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“…Using either mice or rats overexpressing SOD1 or SOD1-knockout mice, it has been shown that SOD1 reduces brain injury after transient global ischemia (Chan et al, 1998;Kawase et al, 1999;Murakami et al, 1997). While most studies focused on hippocampal injury, one study using male transgenic rats, found neuroprotection in caudoputamen similar to the results of our study (Chan et al, 1998).…”

Section: Discussionsupporting

confidence: 79%

SOD1 Overexpression and Female Sex Exhibit Region-Specific Neuroprotection after Global Cerebral Ischemia Due to Cardiac Arrest

Kofler

Hurn

Traystman

2005

J Cereb Blood Flow Metab

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Cardiac arrest is often associated with poor neurologic outcome since therapeutic options are limited. We tested the hypothesis that overexpression of CuZn superoxide dismutase (SOD þ /À) is neuroprotective in a new murine model of cardiac arrest and cardiopulmonary resuscitation (CPR). Second, we investigated if female and male mice sustain similar injury and if sex-specific outcomes are altered by SOD overexpression. Neuronal injury was quantified 3 days after 8 mins of KClinduced cardiac arrest by calculating the percentage of ischemic neurons for caudoputamen and hippocampal CA1 region. In rostral caudoputamen, less neuronal cell loss was found for SOD þ /À mice (31%722%) when compared with wild-type (WT) mice (47%731%, Po0.05). Superoxide dismutase overexpression did not reduce injury in the caudal caudoputamen. No sex-linked protection was evident in either genotype in the caudoputamen. Female WT mice had less CA1 injury than male WT mice (26%731% versus 54%730%, Po0.05), whereas no sex difference was found in SOD þ /À mice (female: 42%729%; male: 37%737%). Comparison of hippocampal injury between genotypes revealed no differences for either males or females. In conclusion, SOD1 overexpression and female sex were associated with significant neuroprotection in this murine cardiac arrest model. However, no additive neuroprotection was observed, and these beneficial effects were restricted to specific brain regions.

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Section: Discussionsupporting

confidence: 79%

SOD1 Overexpression and Female Sex Exhibit Region-Specific Neuroprotection after Global Cerebral Ischemia Due to Cardiac Arrest

Kofler

Hurn

Traystman

2005

J Cereb Blood Flow Metab

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“…Together, with the downstream enzymes catalase and glutathione peroxidase (which convert H 2 O 2 to water and oxygen), SOD1 reduces cellular free radicals. This function is important, because mice lacking the SOD1 gene develop numerous abnormalities, including reduced fertility (17), motor axonopathy (18), increased age-associated loss of cochlear hair cells (19) and neuromuscular junction synapses (20), and enhanced susceptibility to a variety of noxious assaults on the nervous system, such as axonal injury (21), ischemia (22,23), hemolysate exposure (24), and irradiation (25).…”

Section: Amyotrophic Lateral Sclerosis (Als)mentioning

confidence: 99%

Inhibition of Chaperone Activity Is a Shared Property of Several Cu,Zn-Superoxide Dismutase Mutants That Cause Amyotrophic Lateral Sclerosis

Tummala

Jung

Tiwari

et al. 2005

Journal of Biological Chemistry

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron degeneration, paralysis, and death. Mutant Cu,Znsuperoxide dismutase (SOD1) causes a subset of ALS by an unidentified toxic property. Increasing evidence suggests that chaperone dysfunction plays a role in motor neuron degeneration in ALS. To investigate the relationship between mutant SOD1 expression and chaperone dysfunction, we measured chaperone function in central nervous system tissue lysates from normal mice and transgenic mice expressing human SOD1 variants. We observed a significant decrease in chaperone activity in tissues from mice expressing ALS-linked mutant SOD1 but not control mice expressing human wild type SOD1. This decrease was detected only in the spinal cord, became apparent by 60 days of age (before the onset of muscle weakness and significant motor neuron loss), and persisted throughout the late stages. In addition, this impairment of chaperone activity occurred only in cytosolic but not in mitochondrial and nuclear fractions. Furthermore, multiple recombinant human SOD1 mutants with differing biochemical and biophysical properties inhibited chaperone function in a cell-free extract of normal mouse spinal cords. Thus, mutant SOD1 proteins may impair chaperone function independent of gene expression in vivo, and this inhibition may be a shared property of ALS-linked mutant SOD1 proteins.

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“…In mice, expression of mutant SOD1, but not complete elimination of SOD1, causes ALS. Nonetheless, SOD1 -knockout mice show reduced fertility (Matzuk et al ., 1998), motor axonopathy (Shefner et al ., 1999), age-associated loss of cochlear hair cells (McFadden et al ., 2001) and neuromuscular junction synapses , as well as enhanced susceptibility to a variety of noxious assaults on the nervous system, such as axonal injury (Reaume et al ., 1996), ischaemia (Kondo et al ., 1997;Kawase et al ., 1999), haemolysate exposure (Matz et al ., 2000) and irradiation (Behndig et al ., 2001). Given the toxicity of the mutant protein and the functional importance of the wild-type, the ideal therapy for ALS would selectively block expression of the mutant while retaining expression of wild-type protein.…”

Section: Introductionmentioning

confidence: 99%

Selective silencing by RNAi of a dominant allele that causes amyotrophic lateral sclerosis

et al. 2003

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SummaryRNA interference (RNAi) can achieve sequence-selective inactivation of gene expression in a wide variety of eukaryotes by introducing double-stranded RNA corresponding to the target gene. Here we explore the potential of RNAi as a therapy for amyotrophic lateral sclerosis (ALS) caused by mutations in the Cu, Zn superoxide dismutase ( SOD1 ) gene. Although the mutant SOD1 is toxic, the wild-type SOD1 performs important functions. Therefore, the ideal therapeutic strategy should be to selectively inhibit the mutant, but not the wild-type SOD1 expression. Because most SOD1 mutations are single nucleotide changes, to selectively silence the mutant requires singlenucleotide specificity. By coupling rational design of small interfering RNAs (siRNAs) with their validation in RNAi reactions in vitro and in vivo , we have identified siRNA sequences with this specificity. A similarly designed sequence, when expressed as small hairpin RNA (shRNA) under the control of an RNA polymerase III (pol III) promoter, retains the single-nucleotide specificity. Thus, RNAi is a promising therapy for ALS and other disorders caused by dominant, gain-of-function gene mutations.

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Exacerbation of Delayed Cell Injury After Transient Global Ischemia in Mutant Mice With CuZn Superoxide Dismutase Deficiency

Cited by 131 publications

References 36 publications

SOD1 Overexpression and Female Sex Exhibit Region-Specific Neuroprotection after Global Cerebral Ischemia Due to Cardiac Arrest

SOD1 Overexpression and Female Sex Exhibit Region-Specific Neuroprotection after Global Cerebral Ischemia Due to Cardiac Arrest

Inhibition of Chaperone Activity Is a Shared Property of Several Cu,Zn-Superoxide Dismutase Mutants That Cause Amyotrophic Lateral Sclerosis

Selective silencing by RNAi of a dominant allele that causes amyotrophic lateral sclerosis

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